New Drug Approvals

Home » Search results for 'doxorubicin'

Search Results for: doxorubicin

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO .....FOR BLOG HOME CLICK HERE

Blog Stats

  • 3,944,427 hits

Flag and hits

Flag Counter

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,726 other followers

Follow New Drug Approvals on WordPress.com

Archives

Categories

Recent Posts

Flag Counter

ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,726 other followers

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK LIFE SCIENCES LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 PLUS year tenure till date June 2021, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 33 lakh plus views on New Drug Approvals Blog in 233 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

Personal Links

Verified Services

View Full Profile →

Archives

Categories

Flag Counter

Aldoxorubicin…CytRx is pouring money into R&D of cancer-fighting drugs


Aldoxorubicin, DOXO-EMCH

N’-[1-[4(S)-(3-Amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyloxy)-2(S),5,12-trihydroxy-7-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydronaphthacen-2-yl]-2-hydroxyethylidene]-6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanohydrazide

1H-​Pyrrole-​1-​hexanoic acid, 2,​5-​dihydro-​2,​5-​dioxo-​, (2E)​-​2-​[1-​[(2S,​4S)​-​4-​[(3-​amino-​2,​3,​6-​trideoxy-​α-​L-​lyxo– ​hexopyranosyl)​oxy]​-​1,​2,​3,​4,​6,​11-​hexahydro-​2,​5,​12-​ trihydroxy-​7-​methoxy-​6,​11-​dioxo-​2-​naphthacenyl]​-​2-​ hydroxyethylidene]​hydrazide

CytRx is pouring money into R&D of cancer-fighting drugs             see article

Los Angeles Times

s most promising cancer-fighting drug, aldoxorubicin, is “sort of like a guided … Phase 3 clinical trial of a second-line treatment for soft-tissue sarcoma.

 

Aldoxorubicin-INNO206 structure

 

Aldoxorubicin

http://www.ama-assn.org/resources/doc/usan/aldoxorubicin.pdf

 in phase 3         Cytrx Corporation

(E)-N’-(1-((2S,4S)-4-(((2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2,5,12-trihydroxy-7-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-2-yl)-2-hydroxyethylidene)-6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanehydrazide hydrochloride

1H-Pyrrole-1-hexanoic acid, 2,5-dihydro-2,5-dioxo-, (2E)-2-[1-[(2S,4S)-4-[(3-amino-
2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-1,2,3,4,6,11-hexahydro-2,5,12-trihydroxy-
7-methoxy-6,11-dioxo-2-naphthacenyl]-2-hydroxyethylidene]hydrazide

N’-[(1E)-1-{(2S,4S)-4-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-2,5,12-
trihydroxy-7-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-2-yl}-2-
hydroxyethylidene]-6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanohydrazide
MOLECULAR FORMULA C37H42N4O13

MOLECULAR WEIGHT 750.7

SPONSOR CytRx Corp.

CODE DESIGNATION

  • Aldoxorubicin
  • INNO 206
  • INNO-206
  • UNII-C28MV4IM0B

CAS REGISTRY NUMBER 1361644-26-9

CAS:  151038-96-9 (INNO-206); 480998-12-7 (INNO-206 HCl salt),  1361644-26-9

QC data: View NMR, View HPLC, View MS
Safety Data Sheet (MSDS): View Material Safety Data Sheet (MSDS)

hydrochloride


CAS:  151038-96-9

Chemical Formula: C37H42N4O13

Exact Mass: 750.27484

Molecular Weight: 750.75

Certificate of Analysis: View current batch of CoA
QC data: View NMR, View HPLC, View MS
Safety Data Sheet (MSDS): View Material Safety Data Sheet (MSDS)

 

Chemical structure for Aldoxorubicin (USAN)

In vitro protocol: Clin Cancer Res. 2012 Jul 15;18(14):3856-67
In vivo protocol: Clin Cancer Res. 2012 Jul 15;18(14):3856-67.Invest New Drugs. 2010 Feb;28(1):14-9.Invest New Drugs. 2012 Aug;30(4):1743-9.Int J Cancer. 2007 Feb 15;120(4):927-34.
Clinical study: Expert Opin Investig Drugs. 2007 Jun;16(6):855-66.

Aldoxorubicin (INNO-206): Aldoxorubicin, also known as INNO-206,  is the 6-maleimidocaproyl hydrazone derivative prodrug of the anthracycline antibiotic doxorubicin (DOXO-EMCH) with antineoplastic activity. Following intravenous administration, doxorubicin prodrug INNO-206 binds selectively to the cysteine-34 position of albumin via its maleimide moiety. Doxorubicin is released from the albumin carrier after cleavage of the acid-sensitive hydrazone linker within the acidic environment of tumors and, once located intracellularly, intercalates DNA, inhibits DNA synthesis, and induces apoptosis. Albumin tends to accumulate in solid tumors as a result of high metabolic turnover, rapid angiogenesis, hyervasculature, and impaired lymphatic drainage. Because of passive accumulation within tumors, this agent may improve the therapeutic effects of doxorubicin while minimizing systemic toxicity.

“Aldoxorubicin has demonstrated effectiveness against a range of tumors in both human and animal studies, thus we are optimistic in regard to a potential treatment for Kaposi’s sarcoma. The current standard-of-care for severe dermatological and systemic KS is liposomal doxorubicin (Doxil®). However, many patients exhibit minimal to no clinical response to this agent, and that drug has significant toxicity and manufacturing issues,” said CytRx President and CEO Steven A. Kriegsman. “In addition to obtaining valuable information related to Kaposi’s sarcoma, this trial represents another opportunity to validate the value and viability of our linker technology platform.” The company expects to announce Phase-2 study results in the second quarter of 2015.

Kaposi’s sarcoma is an orphan indication, meaning that only a small portion of the population has been diagnosed with the disease (fewer than 200,000 individuals in the country), and in turn, little research and drug development is being conducted to treat and cure it. The FDA’s Orphan Drug Act may grant orphan drug designation to a drug such as aldoxorubicin that treats a rare disease like Kaposi’s sarcoma, offering market exclusivity for seven years, fast-track status in some cases, tax credits, and grant monies to accelerate research

The widely used chemotherapeutic agent doxorubicin is delivered systemically and is highly toxic, which limits its dose to a level below its maximum therapeutic benefit. Doxorubicin also is associated with many side effects, especially the potential for damage to heart muscle at cumulative doses greater than 450 mg/m2. Aldoxorubicin combines doxorubicin with a novel single-molecule linker that binds directly and specifically to circulating albumin, the most plentiful protein in the bloodstream. Protein-hungry tumors concentrate albumin, thus increasing the delivery of the linker molecule with the attached doxorubicin to tumor sites. In the acidic environment of the tumor, but not the neutral environment of healthy tissues, doxorubicin is released. This allows for greater doses (3 1/2 to 4 times) of doxorubicin to be administered while reducing its toxic side effects. In studies thus far there has been no evidence of clinically significant effects of aldoxorubicin on heart muscle, even at cumulative doses of drug well in excess of 2,000 mg/m2.

INNO-206 is an anthracycline in early clinical trials at CytRx Oncology for the treatment of breast cancer, HIV-related Kaposi’s sarcoma, glioblastoma multiforme, stomach cancer and pancreatic cancer. In 2014, a pivotal global phase 3 clinical trial was initiated as second-line treatment in patients with metastatic, locally advanced or unresectable soft tissue sarcomas. The drug candidate was originally developed at Bristol-Myers Squibb, and was subsequently licensed to KTB Tumorforschungs. In August 2006, Innovive Pharmaceuticals (acquired by CytRx in 2008) licensed the patent rights from KTB for the worldwide development and commercialization of the drug candidate. No recent development has been reported for research that had been ongoing for the treatment of small cell lung cancer (SCLC).

INNO-206 is a doxorubicin prodrug. Specifically, it is the 6-maleimidocaproyl hydrazone of doxorubicin. After administration, the drug candidate rapidly binds endogenous circulating albumin through the acid sensitive EMCH linker. Circulating albumin preferentially accumulates in tumors, bypassing uptake by other non-specific sites including the heart, bone marrow and the gastrointestinal tract. Once inside the acidic environment of the tumor cell, the EMCH linker is cleaved and free doxorubicin is released at the tumor site. Like other anthracyclines, doxorubicin inhibits DNA and RNA synthesis by intercalating between base pairs of the DNA/RNA strand, thus preventing the replication of rapidly-growing cancer cells. It also creates iron-mediated free oxygen radicals that damage the DNA and cell membranes. In 2011, orphan drug designation was assigned in the U.S. for the treatment of pancreatic cancer and for the treatment of soft tissue sarcoma.

CytRx Corporation (NASDAQ:CYTR) has  announced it has initiated a pivotal global Phase 3 clinical trial to evaluate the efficacy and safety of aldoxorubicin as a second-line treatment for patients with soft tissue sarcoma (STS) under a Special Protocol Assessment with the FDA. Aldoxorubicin combines the chemotherapeutic agent doxorubicin with a novel linker-molecule that binds specifically to albumin in the blood to allow for delivery of higher amounts of doxorubicin (3.5 to 4 times) without several of the major treatment-limiting toxicities seen with administration of doxorubicin alone.

According to a news from Medicalnewstoday.com; CytRx holds the exclusive worldwide rights to INNO-206. The Company has previously announced plans to initiate Phase 2 proof-of-concept clinical trials in patients with pancreatic cancer, gastric cancer and soft tissue sarcomas, upon the completion of optimizing the formulation of INNO-206. Based on the multiple myeloma interim results, the Company is exploring the possibility of rapidly including multiple myeloma in its INNO-206 clinical development plans.

According to CytRx’s website, In preclinical models, INNO-206 was superior to doxorubicin with regard to ability to increase dosing, antitumor efficacy and safety. A Phase I study of INNO-206 that demonstrated safety and objective clinical responses in a variety of tumor types was completed in the beginning of 2006 and presented at the March 2006 Krebskongress meeting in Berlin. In this study, doses were administered at up to 4 times the standard dosing of doxorubicin without an increase in observed side effects over historically seen levels. Objective clinical responses were seen in patients with sarcoma, breast, and lung cancers.

 INNO-206 – Mechanism of action:

According to CytRx’s website, the proposed mechanism of action is as the follow steps: (1) after administration, INNO-206 rapidly binds endogenous circulating albumin through the EMCH linker. (2) circulating albumin preferentially accumulates in tumors, bypassing uptake by other non-specific sites including heart, bone marrow and gastrointestinal tract; (3) once albumin-bound INNO-206 reaches the tumor, the acidic environment of the tumor causes cleavage of the acid sensitive linker; (4) free doxorubicin is released at the site of the tumor.

INNO-206 – status of clinical trials:

CytRx has announced  that, in December 2011, CytRx initiated its international Phase 2b clinical trial to evaluate the preliminary efficacy and safety of INNO-206 as a first-line therapy in patients with soft tissue sarcoma who are ineligible for surgery. The Phase 2b clinical trial will provide the first direct clinical trial comparison of INNO-206 with native doxorubicin, which is dose-limited due to toxicity, as a first-line therapy. (source:http://cytrx.com/inno_206, accessed date: 02/01/2012).

Results of Phase I study:

In a phase I study a starting dose of 20 mg/m2 doxorubicin equivalents was chosen and 41 patients with advanced cancer disease were treated at dose levels of 20–340 mg/m2 doxorubicin equivalents . Treatment with INNO-206 was well tolerated up to 200 mg/m2 without manifestation of drug-related side effects which is a ~3-fold increase over the standard dose for doxorubicin (60 mg/kg). Myelosuppression and mucositis were the predominant adverse effects at dose levels of 260 mg/m2 and became dose-limiting at 340 mg/m2. 30 of 41 patients were assessable for analysis of response. Partial responses were observed in 3 patients (10%, small cell lung cancer, liposacoma and breast carcinoma). 15 patients (50%) showed a stable disease at different dose levels and 12 patients (40%) had evidence of tumor progression. (source: Invest New Drugs (2010) 28:14–19)

phase 2

CytRx Corporation (CYTR), a biopharmaceutical research and development company specializing in oncology, today announced that its oral presentation given by Sant P. Chawla, M.D., F.R.A.C.P., Director of the Sarcoma Oncology Center, titled “Randomized phase 2b trial comparing first-line treatment with aldoxorubicin versus doxorubicin in patients with advanced soft tissue sarcomas,” was featured in The Lancet Oncology in its July 2014 issue (Volume 15, Issue 8) in a review of the major presentations from the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting.

“We are honored to have been included in The Lancet Oncology’s review of major presentations from ASCO and pleased that these important clinical findings are being recognized by one of the world’s premier oncology journals,” said Steven A. Kriegsman, CytRx President and CEO. “In clinical trials, aldoxorubicin has been shown to be a well-tolerated and efficacious single agent for the treatment of soft tissue sarcoma (STS) that lacks the cardiotoxicity associated with doxorubicin therapy, the current standard of care. We remain on track to report the full overall survival results from this trial prior to year-end 2014.”

The data presented at ASCO 2014 were updated results from CytRx’s ongoing multicenter, randomized, open-label global Phase 2b clinical trial investigating the efficacy and safety of aldoxorubicin compared with doxorubicin as first-line therapy in subjects with metastatic, locally advanced or unresectable STS. The updated trial results demonstrated that aldoxorubicin significantly increases progression-free survival (PFS), PFS at 6 months, overall response rate (ORR) and tumor shrinkage, compared to doxorubicin, the current standard-of-care, as a first-line treatment in patients with STS. The data trended in favor of aldoxorubicin for all of the major subtypes of STS

phase 3

Aldoxorubicin is currently being studied in a pivotal global Phase 3 clinical trial evaluating the efficacy and safety of aldoxorubicin as a second-line treatment for patients with STS under a Special Protocol Assessment with the FDA. CytRx is also conducting two Phase 2 clinical trials evaluating aldoxorubicin in patients with late-stage glioblastoma (GBM) and HIV-related Kaposi’s sarcoma and expects to start a phase 2b study in patients with relapsed small cell lung cancer

 

PATENTS       WO 2000076551, WO 2008138646, WO 2011131314,

…………………….

WO 2014093815

http://www.google.com/patents/WO2014093815A1?cl=en

Anthracyclines are a class of antibiotics derived from certain types of Streptomyces bacteria. Anthracyclines are often used as cancer therapeutics and function in part as nucleic acid intercalating agents and inhibitors of the DNA repair enzyme topoisomerase II, thereby damaging nucleic acids in cancer cells, preventing the cells from replicating. One example of an anthracycline cancer therapeutic is doxorubicin, which is used to treat a variety of cancers including breast cancer, lung cancer, ovarian cancer, lymphoma, and leukemia. The 6-maleimidocaproyl hydrazone of doxorubicin (DOXO-EMCH) was originally synthesized to provide an acid-sensitive linker that could be used to prepare immunoconjugates of doxorubicin and monoclonal antibodies directed against tumor antigens (Willner et al., Bioconjugate Chem 4:521-527 (1993)). In this context, antibody disulfide bonds are reduced with dithiothreitol to form free thiol groups, which in turn react with the maleimide group of DOXO-EMCH to form a stable thioether bond. When administered, the doxorubicin-antibody conjugate is targeted to tumors containing the antigen recognized by the antibody. Following antigen-antibody binding, the conjugate is internalized within the tumor cell and transported to lysosomes. In the acidic lysosomal environment, doxorubicin is released from the conjugate intracellularly by hydrolysis of the acid-sensitive hydrazone linker. Upon release, the doxorubicin reaches the cell nucleus and is able to kill the tumor cell. For additional description of doxorubicin and

DOXO-EMCH see, for example, U.S. Patents 7,387,771 and 7,902,144 and U.S. Patent Application No. 12/619,161, each of which are incorporated in their entirety herein by reference.

[0003] A subsequent use of DOXO-EMCH was developed by reacting the molecule in vitro with the free thiol group (Cys-34) on human serum albumin (HSA) to form a stable thioether conjugate with this circulating protein (Kratz et al, J Med Chem 45:5523-5533 (2002)). Based on these results, it was

hypothesized that intravenously-administered DOXO-EMCH would rapidly conjugate to HSA in vivo and that this macromolecular conjugate would preferentially accumulate in tumors due to an “enhanced permeability and retention” (EPR) intratumor effect (Maeda et al., J Control Release 65:271-284 (2000)).

[0004] Acute and repeat-dose toxicology studies with DOXO-EMCH in mice, rats, and dogs identified no toxicity beyond that associated with doxorubicin, and showed that all three species had significantly higher tolerance for DOXO-EMCH compared to doxorubicin (Kratz et al, Hum Exp Toxicol 26: 19-35 (2007)). Based on the favorable toxicology profile and positive results from animal tumor models, a Phase 1 clinical trial of DOXO-EMCH was conducted in 41 advanced cancer patients (Unger et al, Clin Cancer Res 13:4858-4866 (2007)). This trial found DOXO-EMCH to be safe for clinical use. In some cases, DOXO-EMCH induced tumor regression.

[0005] Due to the sensitivity of the acid-cleavable linker in DOXO-EMCH, it is desirable to have formulations that are stable in long-term storage and during reconstitution (of, e.g., previously lyophilized compositions) and administration. DOXO-EMCH, when present in compositions, diluents and administration fluids used in current formulations, is stable only when kept at low temperatures. The need to maintain DOXO-EMCH at such temperatures presents a major problem in that it forces physicians to administer cold (4°C) DOXO-EMCH compositions to patients. Maintaining DOXO-EMCH at low temperatures complicates its administration in that it requires DOXO-EMCH to be kept at 4°C and diluted at 4°C to prevent degradation that would render it unsuitable for patient use. Further, administration at 4°C can be harmful to patients whose body temperature is significantly higher (37°C).

[0006] Lyophilization has been used to provide a stable formulation for many drugs. However, reconstitution of lyophilized DOXO-EMCH in a liquid that does not maintain stability at room temperature can result in rapid decomposition of DOXO-EMCH. Use of an inappropriate diluent to produce an injectable composition of DOXO-EMCH can lead to decreased stability and/or solubility. This decreased stability manifests itself in the cleavage of the linker between the doxorubicin and EMCH moieties, resulting in degradation of the DOXO-EMCH into two components: doxorubicin and linker-maleimide. Thus, stable,

reconstituted lyophilized solutions of anthracycline-EMCH (e.g., DOXO-EMCH), and injectable compositions containing the same, are required to solve these problems and to provide a suitable administration vehicle that can be used reasonably in treating patients both for clinical trials and commercially.

DOXO-EMCH. The term “DOXO-EMCH,” alone or in combination with any other term, refers to a compound as depicted by the following structure:

 

Figure imgf000011_0001

OH

DOXO-EMCH is also referred to as (E)-N’-(l-((2S,4S)-4-(4-amino-5-hydroxy-6- methyl-tetrahydro-2H-pyran-2-yloxy-2,5 , 12-trihydroxy-7-methoxy-6, 11- dioxol,2,3,4,6,l l-hexahydrotetracen-2-yl)-2-hydroxyethylidene)-6-(2,5-dioxo-2H- pyrrol- 1 (5H)yl)hexanehydrazide»HCl.

………………………………

CN 102675385

http://www.google.com/patents/CN102675385A?cl=en

According to literature reports, (eg see David Willner et al, “(6_Maleimidocaproyl) hydrazoneof Doxorubicm-A New Derivative for the Preparation ofImmunoconjugates oiDoxorubicin,” Bioconjugate Chem. 1993,4, 521-527; JK Tota Hill, etc. man, “The method of preparation of thioether compounds noir,” CN1109886A, etc.), adriamycin 13 – bit hydrazone derivative synthesis and the main process are as follows:

[0004]

Figure CN102675385AD00041

[0005] First, maleic anhydride and 6 – aminocaproic acid was refluxed in a large number of acid reaction ko ni acid I; agent under the action of the ring after the cyclization maleimidocaproic acid 2 (yield 30-40% ), cyclic acid anhydride mixture is generally ko, trimethyl silyl chloride and tri-amines such ko; maleimido aminocaproic acid tert-butyl ester with hydrazine to condensation to give 2 – (6 – aminocaproic maleimido ) hydrazine carboxylic acid tert-butyl ester 3 (yield 70-85%), the condensing agent is N-methylmorpholine and isobutyl chloroformate; 3 in a large number of trifluoroacetic acid deprotection ko maleimido ko has trifluoroacetic acid hydrazide 4 (yield 70%); the doxorubicin hydrochloride salt with a ko in trifluoroacetic acid catalyzed condensation in methanol solvent to doxorubicin hydrazone product was obtained (yield 80%) .

[0006] The synthetic method the yield is low (in particular, by maleic acid imido step 2), the total yield of not more than 20%, and the solvent consumption is large, adriamycin hydrazone product per Malek consumes about ko acid reaction solvent, 70mL, tetrahydrofuran 300mL, ko trifluoroacetic acid 40mL, and because the 2 – (6 – maleimido hexanoyl)-hydrazine carboxylic acid tert-butyl ester was purified by column chromatography required, but also to consume a large amount of Solvent. This has resulted in synthesis post-processing complex process, complicated operation. And because the end product of the synthesis of doxorubicin hydrazone ko using trifluoroacetic acid, inevitably there will be in the product ko trifluoroacetic acid impurities, not divisible. Based on the high cost of such a route exists, yield and production efficiency is low, Eri Arts route operational complexity and other shortcomings, is obviously not suitable for mass production, it is necessary to carry out improvements or exploring other Eri Arts synthesis methods.

doxorubicin hydrazone derivative,

Figure CN102675385AC00021

Wherein n is an integer of 1-15, characterized in that said method comprises the steps of: (1) the maleic acid chloride of the formula H2N-(CH2) n-COOH amino acid I b in the presence of a base prepared by condensation of maleimido group steps I c acid,

Figure CN102675385AC00022

(2) maleic acid imido group I c and then with an acylating reagent of tert-butyl carbazate in the presence of a base in the reaction of step I d,

Figure CN102675385AC00023

(3) I d deprotection with trifluoroacetic acid, the alkali and removing trifluoroacetic acid to obtain the maleimido group I e hydrazide steps

Figure CN102675385AC00024

(4) an imido group of maleic hydrazide I e and doxorubicin hydrochloride catalyzed condensation of hydrogen chloride to obtain a final product hydrazone derivative of doxorubicin,

Figure CN102675385AC00031

[0028]

Figure CN102675385AD00073
Figure CN102675385AD00091

[0049] The butene-ni chloride 15. 2g (0. Imol) was dissolved in 25mL of chloroform was dried by adding anhydrous potassium carbonate 27. 6g (0. 2mol), the gas and gas protection and conditions of 0 ° C was added dropwise 6 – aminocaproic acid 13. 2g (0. ImoI) in chloroform (50mL) solution, add after reaction at room temperature for 3 hours. Washed with saturated brine, dried over anhydrous magnesium sulfate, suction filtered, concentrated under reduced pressure. The residue was recrystallized from alcohol ko maleimido acid (Compound c) 18. 8g, 90% yield, m.p. :85-87 ° C.

[0050] Compound c 10. 5g (50mmol) and thionyl chloride crab 5. 3mL (75mmol) was heated under reflux the mixture I. 5 hours and concentrated under reduced pressure in an argon atmosphere under the conditions of 0 ° C and added dropwise to the hydrazine carboxylic acid tert-butyl ester 6.6g (50mmol) amine with a three ko

10. 8mL (75mmol) in anhydrous ko ether (50mL) solution added after the reaction was continued at room temperature for I. 5 hours. Washed with 5% hydrochloric acid, 5% sodium bicarbonate, and saturated brine, dried over anhydrous magnesium sulfate overnight, filtered with suction to give the compound of d ko ether solution. The solution was cooled to 0 ° C, was added dropwise trifluoroacetic acid ko 7. 4mL (100mmOl), After the addition the reaction was continued for 10 minutes, suction filtered, the filter cake was washed twice with ether, ko and dried in vacuo to give 6 – maleic acid sub-aminocaproic acid hydrazide trifluoro-ko 12. 2g, 72% yield, m.p. 99-102 ° C. IOmL this salt is added to sodium hydroxide (10%) solution, stirred for a while, with ko extracted with ether, the organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated to give 6 – aminocaproic maleimido hydrazide (compound e) 7. Sg, 70% yield.

[0051] The doxorubicin hydrochloride 0. 58g (Immol) with compound e 0. 45g (2mmol) was dissolved in 150mL of anhydrous methanol, passing about 2mmol of dry hydrogen chloride, under argon, at room temperature protected from light and reaction conditions 24 inches. Concentrated under reduced pressure at room temperature, the solid was washed with about IOOmL ko nitrile, and dried in vacuo doxorubicin 6 – aminocaproic maleimido hydrazone O. 63g, 80% yield. 1H NMR (CD3OD) δ: 7. 94 (bd, 1H), 7. 82 (t, 1H), 7. 55 (d, 1H), 6. 78 (s, 2H), 5. 48 (s, 1H ), 5. 07 (t, 1H), 4 · 59 (d, 1H), 4 · 21 (m, 1Η), 4 · 02 (s, 3H), 3 · 63-3. 30 (m, 5H) , 2 · 55-2. 26 (m, 4H), 2. 19-1. 88 (m, 3Η), I. 69-1. 18 (m, 12Η, I. 26). [0052] Although specific reference to the above embodiments of the present invention will be described, it will be understood that in the appended claims without departing from the invention as defined by the spirit and scope of the skilled person can be variously truncated, substitutions and changes. Accordingly, the present invention encompasses these deletions, substitutions and changes.

………………………………….

US 5622929

http://www.google.co.in/patents/US5622929

OR

http://www.google.co.in/patents/EP0554708A1

Method A:

Figure imgb0027

As noted below, Method A is the preferred method when the Michael Addition Receptor is a maleimido moiety.

[0077]

Alternatively, the Formula (IIa) compound may be prepared by reaction of the drug with a hydrazide to form an intermediate hydrazone drug derivative followed by reaction of this compound with a Michael Addition Receptor containing moiety according to the general process described in Method B:

Figure imgb0028

…………………………………….

http://www.google.co.in/patents/WO2012167255A1?cl=en

Synthesis of DOXO-EMCH

The synthesis of DOXO-EMCH was done initially in accordance with that previously published by Willner and co-workers (Bioconjugate Chem., 4:521-527, 1993). Problems arose in the initial addition of the 6-maleimidocaproylhydrazine to the C-13 ketone of doxorubicin. HPLC results did not give a good yield of product, only 50-60%. Upon further analysis, we determined TFA was not needed to catalyze the reaction, and instead used pyridine. With pyridine, chromatograms from the HPLC showed 90% DOXO-EMCH relative to 10% DOX. The pyridine may have improved the yield by serving as a base to facilitate formation of the hydrazone. Another problem we encountered in the synthesis was purification of the final product. According to Willner’ s method, 5 volumes of acetonitrile (ACN) were to be added to a concentrated methanolic solution of crude DOXO-EMCH to achieve crystallization after 48 h at 4 °C. By this method, only 10-20%) of the desired product precipitated. To obtain a better yield, the crystallization step was done 4 times with 6 volumes of ACN used in each step. A lesser amount of methanol was needed each time, as less product remained in solution. Even with the multiple crystallizations, a final yield of only 59% was obtained. Various other methods for crystallization were explored, including using different solvents and increasing the initial solubility in methanol by heat, but none gave better results. 1.2 Rate of Hydrolysis of DOXO-EMCH at Varying pH

Subsequent pH studies to determine the rate of hydrolysis of the hydrazone were carried out as a benchmark for later hydrolysis experiments with PPD-EMCH. The results of the hydrolysis experiments showed that at lower pH, the hydrolysis reaction proceeded very quickly in the formation of DOX. Moreover, at higher pH the hydrazone proved to be very robust in that its degradation is very slow.

 

General HPLC instruments and methods

Analytical HPLC methods were performed using a Hewlett-Packard/ Aligent 1050/1100 chromatograph with an auto injector, diode array UV-vis absorption detector. Method 1.1 : Analytical HPLC injections were onto an Aligent Zorbax Eclipse XDB-C18 reversed phase column, 4.6 mm x 150 mm, eluting at 1.0 mL/min. A gradient of acetonitrile/20 mM sodium phosphate buffer (pH 6.9), 80% buffer to 55% at 10 min, 55% to 40% at 12 min, 40% to 80% at 13 min. Retention times: at 480 nm, DOX (9.4 min), DOXO-EMCH (1 1.2 min).

Synthesis of DOXO-EMCH

The synthesis of DOXO-EMCH was accomplished using the procedure reported by Willner et al, with several changes to improve the yield (Willner, D., et al.,

Bioconjugate Chem., 4:521-27, 1993). DOX’HCl (20 mg, 34 μιηοΐ) was dissolved in 6 mL of methanol. Pyridine (12.53 μί) was added to the solution, followed by 35.4 mg

EMCH’TFA. The reaction was stirred at room temperature overnight. By HPLC, the reaction was 90% complete. The solvent was evaporated to dryness by rotary evaporation. A minimal amount of methanol was used to dissolve the solid, and six volumes of acetonitrile at 4 °C were added to the solution. The resulting solution was allowed to sit undisturbed at 4 °C for 48 h for crystallization. The precipitate was collected, and the crystallization method was repeated 4 times. The resulting solids were combined and washed three times with 1 : 10 methanokacetonitrile. The final yield of DOXO-EMCH was 11.59 mg, 58%. HPLC Method 1.1 was used. NMR spectra corresponded to those previously given by Willner (Bioconjugate Chem. 4:521-27. 1993).

…………………………….

http://www.google.co.in/patents/US20070219351

DOXO-EMCH, the structural formula of which is shown below,

Figure US20070219351A1-20070920-C00001

…………………………………

SEE

(6-Maleimidocaproyl)hydrazone of doxorubicin – A new derivative for the preparation of immunoconjugates of doxorubicin
Bioconjugate Chem 1993, 4(6): 521

References

1: Kratz F, Azab S, Zeisig R, Fichtner I, Warnecke A. Evaluation of combination therapy schedules of doxorubicin and an acid-sensitive albumin-binding prodrug of doxorubicin in the MIA PaCa-2 pancreatic xenograft model. Int J Pharm. 2013 Jan 30;441(1-2):499-506. doi: 10.1016/j.ijpharm.2012.11.003. Epub 2012 Nov 10. PubMed PMID: 23149257.

2: Walker L, Perkins E, Kratz F, Raucher D. Cell penetrating peptides fused to a thermally targeted biopolymer drug carrier improve the delivery and antitumor efficacy of an acid-sensitive doxorubicin derivative. Int J Pharm. 2012 Oct 15;436(1-2):825-32. doi: 10.1016/j.ijpharm.2012.07.043. Epub 2012 Jul 28. PubMed PMID: 22850291; PubMed Central PMCID: PMC3465682.

3: Kratz F, Warnecke A. Finding the optimal balance: challenges of improving conventional cancer chemotherapy using suitable combinations with nano-sized drug delivery systems. J Control Release. 2012 Dec 10;164(2):221-35. doi: 10.1016/j.jconrel.2012.05.045. Epub 2012 Jun 13. PubMed PMID: 22705248.

4: Sanchez E, Li M, Wang C, Nichols CM, Li J, Chen H, Berenson JR. Anti-myeloma effects of the novel anthracycline derivative INNO-206. Clin Cancer Res. 2012 Jul 15;18(14):3856-67. doi: 10.1158/1078-0432.CCR-11-3130. Epub 2012 May 22. PubMed PMID: 22619306.

5: Kratz F, Elsadek B. Clinical impact of serum proteins on drug delivery. J Control Release. 2012 Jul 20;161(2):429-45. doi: 10.1016/j.jconrel.2011.11.028. Epub 2011 Dec 1. Review. PubMed PMID: 22155554.

6: Elsadek B, Kratz F. Impact of albumin on drug delivery–new applications on the horizon. J Control Release. 2012 Jan 10;157(1):4-28. doi: 10.1016/j.jconrel.2011.09.069. Epub 2011 Sep 16. Review. PubMed PMID: 21959118.

7: Kratz F, Fichtner I, Graeser R. Combination therapy with the albumin-binding prodrug of doxorubicin (INNO-206) and doxorubicin achieves complete remissions and improves tolerability in an ovarian A2780 xenograft model. Invest New Drugs. 2012 Aug;30(4):1743-9. doi: 10.1007/s10637-011-9686-5. Epub 2011 May 18. PubMed PMID: 21590366.

8: Boga C, Fiume L, Baglioni M, Bertucci C, Farina C, Kratz F, Manerba M, Naldi M, Di Stefano G. Characterisation of the conjugate of the (6-maleimidocaproyl)hydrazone derivative of doxorubicin with lactosaminated human albumin by 13C NMR spectroscopy. Eur J Pharm Sci. 2009 Oct 8;38(3):262-9. doi: 10.1016/j.ejps.2009.08.001. Epub 2009 Aug 18. PubMed PMID: 19695327.

9: Graeser R, Esser N, Unger H, Fichtner I, Zhu A, Unger C, Kratz F. INNO-206, the (6-maleimidocaproyl hydrazone derivative of doxorubicin), shows superior antitumor efficacy compared to doxorubicin in different tumor xenograft models and in an orthotopic pancreas carcinoma model. Invest New Drugs. 2010 Feb;28(1):14-9. doi: 10.1007/s10637-008-9208-2. Epub 2009 Jan 8. PubMed PMID: 19148580.

10: Kratz F. Albumin as a drug carrier: design of prodrugs, drug conjugates and nanoparticles. J Control Release. 2008 Dec 18;132(3):171-83. doi: 10.1016/j.jconrel.2008.05.010. Epub 2008 May 17. Review. PubMed PMID: 18582981.

11: Unger C, Häring B, Medinger M, Drevs J, Steinbild S, Kratz F, Mross K. Phase I and pharmacokinetic study of the (6-maleimidocaproyl)hydrazone derivative of doxorubicin. Clin Cancer Res. 2007 Aug 15;13(16):4858-66. PubMed PMID: 17699865.

12: Lebrecht D, Walker UA. Role of mtDNA lesions in anthracycline cardiotoxicity. Cardiovasc Toxicol. 2007;7(2):108-13. Review. PubMed PMID: 17652814.

13: Kratz F. DOXO-EMCH (INNO-206): the first albumin-binding prodrug of doxorubicin to enter clinical trials. Expert Opin Investig Drugs. 2007 Jun;16(6):855-66. Review. PubMed PMID: 17501697.

14: Kratz F, Ehling G, Kauffmann HM, Unger C. Acute and repeat-dose toxicity studies of the (6-maleimidocaproyl)hydrazone derivative of doxorubicin (DOXO-EMCH), an albumin-binding prodrug of the anticancer agent doxorubicin. Hum Exp Toxicol. 2007 Jan;26(1):19-35. PubMed PMID: 17334177.

15: Lebrecht D, Geist A, Ketelsen UP, Haberstroh J, Setzer B, Kratz F, Walker UA. The 6-maleimidocaproyl hydrazone derivative of doxorubicin (DOXO-EMCH) is superior to free doxorubicin with respect to cardiotoxicity and mitochondrial damage. Int J Cancer. 2007 Feb 15;120(4):927-34. PubMed PMID: 17131338.

16: Di Stefano G, Lanza M, Kratz F, Merina L, Fiume L. A novel method for coupling doxorubicin to lactosaminated human albumin by an acid sensitive hydrazone bond: synthesis, characterization and preliminary biological properties of the conjugate. Eur J Pharm Sci. 2004 Dec;23(4-5):393-7. PubMed PMID: 15567293.

 

EP0169111A1 * Jun 18, 1985 Jan 22, 1986 Sanofi Cytotoxic conjugates useful in therapy, and process for obtaining them
EP0269188A2 * Jun 18, 1985 Jun 1, 1988 Elf Sanofi Cytotoxic conjugates useful in therapy, and process for obtaining them
EP0306943A2 * Sep 8, 1988 Mar 15, 1989 Neorx Corporation Immunconjugates joined by thioether bonds having reduced toxicity and improved selectivity
EP0328147A2 * Feb 10, 1989 Aug 16, 1989 Bristol-Myers Squibb Company Anthracycline immunoconjugates having a novel linker and methods for their production
EP0398305A2 * May 16, 1990 Nov 22, 1990 Bristol-Myers Squibb Company Anthracycline conjugates having a novel linker and methods for their production
EP0457250A2 * May 13, 1991 Nov 21, 1991 Bristol-Myers Squibb Company Novel bifunctional linking compounds, conjugates and methods for their production

KEY words

Aldoxorubicin, CytRx, CANCER, INNO-206, PHASE 3, oncology,  Soft Tissue Sarcoma

 

ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

 

Aldoxorubicin…….Treatment of cancer …HIV-derived Kaposi’s Sarcoma, pancreatic cancer and for the treatment of soft tissue sarcoma.


 

 

Aldoxorubicin-INNO206 structure

 

Aldoxorubicin

Click to access aldoxorubicin.pdf

 in phase 3

(E)-N’-(1-((2S,4S)-4-(((2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2,5,12-trihydroxy-7-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-2-yl)-2-hydroxyethylidene)-6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanehydrazide hydrochloride

1H-Pyrrole-1-hexanoic acid, 2,5-dihydro-2,5-dioxo-, (2E)-2-[1-[(2S,4S)-4-[(3-amino-
2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-1,2,3,4,6,11-hexahydro-2,5,12-trihydroxy-
7-methoxy-6,11-dioxo-2-naphthacenyl]-2-hydroxyethylidene]hydrazide

N’-[(1E)-1-{(2S,4S)-4-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-2,5,12-
trihydroxy-7-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-2-yl}-2-
hydroxyethylidene]-6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanohydrazide
MOLECULAR FORMULA C37H42N4O13

MOLECULAR WEIGHT 750.7

SPONSOR CytRx Corp.

CODE DESIGNATION INNO-206

CAS REGISTRY NUMBER 1361644-26-9

CAS:  151038-96-9 (INNO-206); 480998-12-7 (INNO-206 HCl salt),  1361644-26-9

hydrochloride


CAS:  151038-96-9

Chemical Formula: C37H42N4O13

Exact Mass: 750.27484

Molecular Weight: 750.75

Certificate of Analysis:

View current batch of CoA

QC data:

View NMR, View HPLC, View MS

Safety Data Sheet (MSDS):

View Material Safety Data Sheet (MSDS)

In vitro protocol:

Clin Cancer Res. 2012 Jul 15;18(14):3856-67

In vivo protocol:

Clin Cancer Res. 2012 Jul 15;18(14):3856-67.

Invest New Drugs. 2010 Feb;28(1):14-9.

Invest New Drugs. 2012 Aug;30(4):1743-9.

Int J Cancer. 2007 Feb 15;120(4):927-34.

Clinical study:

Expert Opin Investig Drugs. 2007 Jun;16(6):855-66.

Aldoxorubicin (INNO-206): Aldoxorubicin, also known as INNO-206,  is the 6-maleimidocaproyl hydrazone derivative prodrug of the anthracycline antibiotic doxorubicin (DOXO-EMCH) with antineoplastic activity. Following intravenous administration, doxorubicin prodrug INNO-206 binds selectively to the cysteine-34 position of albumin via its maleimide moiety. Doxorubicin is released from the albumin carrier after cleavage of the acid-sensitive hydrazone linker within the acidic environment of tumors and, once located intracellularly, intercalates DNA, inhibits DNA synthesis, and induces apoptosis. Albumin tends to accumulate in solid tumors as a result of high metabolic turnover, rapid angiogenesis, hyervasculature, and impaired lymphatic drainage. Because of passive accumulation within tumors, this agent may improve the therapeutic effects of doxorubicin while minimizing systemic toxicity.

“Aldoxorubicin has demonstrated effectiveness against a range of tumors in both human and animal studies, thus we are optimistic in regard to a potential treatment for Kaposi’s sarcoma. The current standard-of-care for severe dermatological and systemic KS is liposomal doxorubicin (Doxil®). However, many patients exhibit minimal to no clinical response to this agent, and that drug has significant toxicity and manufacturing issues,” said CytRx President and CEO Steven A. Kriegsman. “In addition to obtaining valuable information related to Kaposi’s sarcoma, this trial represents another opportunity to validate the value and viability of our linker technology platform.” The company expects to announce Phase-2 study results in the second quarter of 2015.

Kaposi’s sarcoma is an orphan indication, meaning that only a small portion of the population has been diagnosed with the disease (fewer than 200,000 individuals in the country), and in turn, little research and drug development is being conducted to treat and cure it. The FDA’s Orphan Drug Act may grant orphan drug designation to a drug such as aldoxorubicin that treats a rare disease like Kaposi’s sarcoma, offering market exclusivity for seven years, fast-track status in some cases, tax credits, and grant monies to accelerate research

INNO-206 is an anthracycline in early clinical trials at CytRx Oncology for the treatment of breast cancer, HIV-related Kaposi’s sarcoma, glioblastoma multiforme, stomach cancer and pancreatic cancer. In 2014, a pivotal global phase 3 clinical trial was initiated as second-line treatment in patients with metastatic, locally advanced or unresectable soft tissue sarcomas. The drug candidate was originally developed at Bristol-Myers Squibb, and was subsequently licensed to KTB Tumorforschungs. In August 2006, Innovive Pharmaceuticals (acquired by CytRx in 2008) licensed the patent rights from KTB for the worldwide development and commercialization of the drug candidate. No recent development has been reported for research that had been ongoing for the treatment of small cell lung cancer (SCLC).

INNO-206 is a doxorubicin prodrug. Specifically, it is the 6-maleimidocaproyl hydrazone of doxorubicin. After administration, the drug candidate rapidly binds endogenous circulating albumin through the acid sensitive EMCH linker. Circulating albumin preferentially accumulates in tumors, bypassing uptake by other non-specific sites including the heart, bone marrow and the gastrointestinal tract. Once inside the acidic environment of the tumor cell, the EMCH linker is cleaved and free doxorubicin is released at the tumor site. Like other anthracyclines, doxorubicin inhibits DNA and RNA synthesis by intercalating between base pairs of the DNA/RNA strand, thus preventing the replication of rapidly-growing cancer cells. It also creates iron-mediated free oxygen radicals that damage the DNA and cell membranes. In 2011, orphan drug designation was assigned in the U.S. for the treatment of pancreatic cancer and for the treatment of soft tissue sarcoma.

CytRx Corporation (NASDAQ:CYTR) has  announced it has initiated a pivotal global Phase 3 clinical trial to evaluate the efficacy and safety of aldoxorubicin as a second-line treatment for patients with soft tissue sarcoma (STS) under a Special Protocol Assessment with the FDA. Aldoxorubicin combines the chemotherapeutic agent doxorubicin with a novel linker-molecule that binds specifically to albumin in the blood to allow for delivery of higher amounts of doxorubicin (3.5 to 4 times) without several of the major treatment-limiting toxicities seen with administration of doxorubicin alone.

According to a news from Medicalnewstoday.com; CytRx holds the exclusive worldwide rights to INNO-206. The Company has previously announced plans to initiate Phase 2 proof-of-concept clinical trials in patients with pancreatic cancer, gastric cancer and soft tissue sarcomas, upon the completion of optimizing the formulation of INNO-206. Based on the multiple myeloma interim results, the Company is exploring the possibility of rapidly including multiple myeloma in its INNO-206 clinical development plans.

According to CytRx’s website, In preclinical models, INNO-206 was superior to doxorubicin with regard to ability to increase dosing, antitumor efficacy and safety. A Phase I study of INNO-206 that demonstrated safety and objective clinical responses in a variety of tumor types was completed in the beginning of 2006 and presented at the March 2006 Krebskongress meeting in Berlin. In this study, doses were administered at up to 4 times the standard dosing of doxorubicin without an increase in observed side effects over historically seen levels. Objective clinical responses were seen in patients with sarcoma, breast, and lung cancers.

 INNO-206 – Mechanism of action:

According to CytRx’s website, the proposed mechanism of action is as the follow steps: (1) after administration, INNO-206 rapidly binds endogenous circulating albumin through the EMCH linker. (2) circulating albumin preferentially accumulates in tumors, bypassing uptake by other non-specific sites including heart, bone marrow and gastrointestinal tract; (3) once albumin-bound INNO-206 reaches the tumor, the acidic environment of the tumor causes cleavage of the acid sensitive linker; (4) free doxorubicin is released at the site of the tumor.

INNO-206 – status of clinical trials:

CytRx has announced  that, in December 2011, CytRx initiated its international Phase 2b clinical trial to evaluate the preliminary efficacy and safety of INNO-206 as a first-line therapy in patients with soft tissue sarcoma who are ineligible for surgery. The Phase 2b clinical trial will provide the first direct clinical trial comparison of INNO-206 with native doxorubicin, which is dose-limited due to toxicity, as a first-line therapy. (source:http://cytrx.com/inno_206, accessed date: 02/01/2012).

   

Results of Phase I study:

In a phase I study a starting dose of 20 mg/m2 doxorubicin equivalents was chosen and 41 patients with advanced cancer disease were treated at dose levels of 20–340 mg/m2 doxorubicin equivalents . Treatment with INNO-206 was well tolerated up to 200 mg/m2 without manifestation of drug-related side effects which is a ~3-fold increase over the standard dose for doxorubicin (60 mg/kg). Myelosuppression and mucositis were the predominant adverse effects at dose levels of 260 mg/m2 and became dose-limiting at 340 mg/m2. 30 of 41 patients were assessable for analysis of response. Partial responses were observed in 3 patients (10%, small cell lung cancer, liposacoma and breast carcinoma). 15 patients (50%) showed a stable disease at different dose levels and 12 patients (40%) had evidence of tumor progression. (source: Invest New Drugs (2010) 28:14–19)

References

1: Kratz F, Azab S, Zeisig R, Fichtner I, Warnecke A. Evaluation of combination therapy schedules of doxorubicin and an acid-sensitive albumin-binding prodrug of doxorubicin in the MIA PaCa-2 pancreatic xenograft model. Int J Pharm. 2013 Jan 30;441(1-2):499-506. doi: 10.1016/j.ijpharm.2012.11.003. Epub 2012 Nov 10. PubMed PMID: 23149257.

2: Walker L, Perkins E, Kratz F, Raucher D. Cell penetrating peptides fused to a thermally targeted biopolymer drug carrier improve the delivery and antitumor efficacy of an acid-sensitive doxorubicin derivative. Int J Pharm. 2012 Oct 15;436(1-2):825-32. doi: 10.1016/j.ijpharm.2012.07.043. Epub 2012 Jul 28. PubMed PMID: 22850291; PubMed Central PMCID: PMC3465682.

3: Kratz F, Warnecke A. Finding the optimal balance: challenges of improving conventional cancer chemotherapy using suitable combinations with nano-sized drug delivery systems. J Control Release. 2012 Dec 10;164(2):221-35. doi: 10.1016/j.jconrel.2012.05.045. Epub 2012 Jun 13. PubMed PMID: 22705248.

4: Sanchez E, Li M, Wang C, Nichols CM, Li J, Chen H, Berenson JR. Anti-myeloma effects of the novel anthracycline derivative INNO-206. Clin Cancer Res. 2012 Jul 15;18(14):3856-67. doi: 10.1158/1078-0432.CCR-11-3130. Epub 2012 May 22. PubMed PMID: 22619306.

5: Kratz F, Elsadek B. Clinical impact of serum proteins on drug delivery. J Control Release. 2012 Jul 20;161(2):429-45. doi: 10.1016/j.jconrel.2011.11.028. Epub 2011 Dec 1. Review. PubMed PMID: 22155554.

6: Elsadek B, Kratz F. Impact of albumin on drug delivery–new applications on the horizon. J Control Release. 2012 Jan 10;157(1):4-28. doi: 10.1016/j.jconrel.2011.09.069. Epub 2011 Sep 16. Review. PubMed PMID: 21959118.

7: Kratz F, Fichtner I, Graeser R. Combination therapy with the albumin-binding prodrug of doxorubicin (INNO-206) and doxorubicin achieves complete remissions and improves tolerability in an ovarian A2780 xenograft model. Invest New Drugs. 2012 Aug;30(4):1743-9. doi: 10.1007/s10637-011-9686-5. Epub 2011 May 18. PubMed PMID: 21590366.

8: Boga C, Fiume L, Baglioni M, Bertucci C, Farina C, Kratz F, Manerba M, Naldi M, Di Stefano G. Characterisation of the conjugate of the (6-maleimidocaproyl)hydrazone derivative of doxorubicin with lactosaminated human albumin by 13C NMR spectroscopy. Eur J Pharm Sci. 2009 Oct 8;38(3):262-9. doi: 10.1016/j.ejps.2009.08.001. Epub 2009 Aug 18. PubMed PMID: 19695327.

9: Graeser R, Esser N, Unger H, Fichtner I, Zhu A, Unger C, Kratz F. INNO-206, the (6-maleimidocaproyl hydrazone derivative of doxorubicin), shows superior antitumor efficacy compared to doxorubicin in different tumor xenograft models and in an orthotopic pancreas carcinoma model. Invest New Drugs. 2010 Feb;28(1):14-9. doi: 10.1007/s10637-008-9208-2. Epub 2009 Jan 8. PubMed PMID: 19148580.

10: Kratz F. Albumin as a drug carrier: design of prodrugs, drug conjugates and nanoparticles. J Control Release. 2008 Dec 18;132(3):171-83. doi: 10.1016/j.jconrel.2008.05.010. Epub 2008 May 17. Review. PubMed PMID: 18582981.

11: Unger C, Häring B, Medinger M, Drevs J, Steinbild S, Kratz F, Mross K. Phase I and pharmacokinetic study of the (6-maleimidocaproyl)hydrazone derivative of doxorubicin. Clin Cancer Res. 2007 Aug 15;13(16):4858-66. PubMed PMID: 17699865.

12: Lebrecht D, Walker UA. Role of mtDNA lesions in anthracycline cardiotoxicity. Cardiovasc Toxicol. 2007;7(2):108-13. Review. PubMed PMID: 17652814.

13: Kratz F. DOXO-EMCH (INNO-206): the first albumin-binding prodrug of doxorubicin to enter clinical trials. Expert Opin Investig Drugs. 2007 Jun;16(6):855-66. Review. PubMed PMID: 17501697.

14: Kratz F, Ehling G, Kauffmann HM, Unger C. Acute and repeat-dose toxicity studies of the (6-maleimidocaproyl)hydrazone derivative of doxorubicin (DOXO-EMCH), an albumin-binding prodrug of the anticancer agent doxorubicin. Hum Exp Toxicol. 2007 Jan;26(1):19-35. PubMed PMID: 17334177.

15: Lebrecht D, Geist A, Ketelsen UP, Haberstroh J, Setzer B, Kratz F, Walker UA. The 6-maleimidocaproyl hydrazone derivative of doxorubicin (DOXO-EMCH) is superior to free doxorubicin with respect to cardiotoxicity and mitochondrial damage. Int J Cancer. 2007 Feb 15;120(4):927-34. PubMed PMID: 17131338.

16: Di Stefano G, Lanza M, Kratz F, Merina L, Fiume L. A novel method for coupling doxorubicin to lactosaminated human albumin by an acid sensitive hydrazone bond: synthesis, characterization and preliminary biological properties of the conjugate. Eur J Pharm Sci. 2004 Dec;23(4-5):393-7. PubMed PMID: 15567293.

 

EP0169111A1 * Jun 18, 1985 Jan 22, 1986 Sanofi Cytotoxic conjugates useful in therapy, and process for obtaining them
EP0269188A2 * Jun 18, 1985 Jun 1, 1988 Elf Sanofi Cytotoxic conjugates useful in therapy, and process for obtaining them
EP0306943A2 * Sep 8, 1988 Mar 15, 1989 Neorx Corporation Immunconjugates joined by thioether bonds having reduced toxicity and improved selectivity
EP0328147A2 * Feb 10, 1989 Aug 16, 1989 Bristol-Myers Squibb Company Anthracycline immunoconjugates having a novel linker and methods for their production
EP0398305A2 * May 16, 1990 Nov 22, 1990 Bristol-Myers Squibb Company Anthracycline conjugates having a novel linker and methods for their production
EP0457250A2 * May 13, 1991 Nov 21, 1991 Bristol-Myers Squibb Company Novel bifunctional linking compounds, conjugates and methods for their production

Sun Pharma Global FZE, First Generic Version of Cancer Drug Doxil (doxorubicin hydrochloride liposome injection) Approved


Sun Pharma Global FZE drug, approved by USFDA

DOXIL (doxorubicin HCl liposome injection) is doxorubicin hydrochloride (HCl) encapsulated in STEALTH® liposomes for intravenous administration.

Doxorubicin is an anthracycline topoisomerase inhibitor isolated from Streptomyces peucetius var. caesius.

Doxorubicin HCl, which is the established name for (8S,10S)-10-[(3-amino-2,3,6-trideoxyα- L-lyxo-hexopyranosyl)oxy]-8-glycolyl-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy5,12- naphthacenedione hydrochloride, has the following structure:

DOXIL® (doxorubicin HCl) Structural Formula Illustration

The molecular formula of the drug is C27H29NO11•HCl; its molecular weight is 579.99.

DOXIL (doxorubicin hcl liposome injection) is provided as a sterile, translucent, red liposomal dispersion in 10-mL or 30-Ml glass, single use vials. Each vial contains 20 mg or 50 mg doxorubicin HCl at a concentration of 2 mg/mL and a pH of 6.5. The STEALTH® liposome carriers are composed of N-(carbonyl-methoxypolyethylene glycol 2000)-1,2-distearoyl-sn-glycero3- phosphoethanolamine sodium salt (MPEG-DSPE), 3.19 mg/mL; fully hydrogenated soy phosphatidylcholine (HSPC), 9.58 mg/mL; and cholesterol, 3.19 mg/mL. Each mL also contains ammonium sulfate, approximately 2 mg; histidine as a buffer; hydrochloric acid and/or sodium hydroxide for pH control; and sucrose to maintain isotonicity. Greater than 90% of the drug is encapsulated in the STEALTH® liposomes

MONDAY Feb. 4, 2013 — The first generic version of the cancer drug Doxil (doxorubicin hydrochloride liposome injection) has been approved by the U.S. Food and Drug Administration, which says the action should help relieve shortages of the brand-name medication.

Doxil is on the agency’s drug shortage list. The list empowers the FDA’s Office of Generic Drugs to grant priority review to generic equivalents, the agency said Monday in a news release.

Noting that generics were of the same quality and strength as the original drugs, the FDA said: “Generic manufacturing and packaging sites must pass the same quality standards as those of brand-name drugs.”

Generic Doxil will be produced by Sun Pharma Global FZE in 20 milligram and 50 milligram vials.

Fam-trastuzumab deruxtecan-nxki


Fam-trastuzumab deruxtecan-nxki

FormulaC6460H9972N1724O2014S44. (C52H57FN9O13)8
CAS1826843-81-5
Mol weight153701.9811
Antineoplastic
  DiseaseBreast cancer (HER2 positive)

DS-8201a

Trastuzumab deruxtecan, sold under the brand name Enhertu, is an antibody-drug conjugate consisting of the humanized monoclonal antibody trastuzumab (Herceptin) covalently linked to the topoisomerase I inhibitor deruxtecan (a derivative of exatecan).[5][6] It is licensed for the treatment of breast cancer or gastric or gastroesophageal adenocarcinoma.[6][7] Trastuzumab binds to and blocks signaling through epidermal growth factor receptor 2 (HER2/neu) on cancers that rely on it for growth. Additionally, once bound to HER2 receptors, the antibody is internalized by the cell, carrying the bound deruxtecan along with it, where it interferes with the cell’s ability to make DNA structural changes and replicate its DNA during cell division, leading to DNA damage when the cell attempts to replicate itself, destroying the cell.[7]

It was approved for medical use in the United States in December 2019,[6] in Japan in March 2020,[8] in the European Union in January 2021,[3][4] and in Australia in October 2021.[1]

Trastuzumab Deruxtecan

Trastuzumab deruxtecan (DS-8201a) is a HER2-targeting antibody-drug conjugate or ADC), structurally composed of a humanized anti-human HER2 (anti-hHER2) antibody, an enzymatically cleavable peptide-linker, and a proprietary topoisomerase I inhibitor payload (exatecan derivative or DX-8951 / DXd).

CLIP

Trastuzumab deruxtecan active substance, also referred to as DS-8201a, results from the conjugation of the following intermediates: – Trastuzumab monoclonal antibody (MAAL-9001); – A drug-linker (MAAA-1162a) comprised of a Topoisomerase I inhibitor derivative of exatecan (MAAA1181a) and a tetrapeptide based cleavable linker (MFAH). MAAL-9001 is covalently conjugated to approximately 8 molecules of MAAA-1162a. The linker is designed to be stable in plasma to reduce systemic exposure to the released MAAA-1181a drug. After cell internalisation, the released MAAA-1181a drug leads to apoptosis of the target tumour cells via the inhibition of topoisomerase I. The released MAAA-1181a drug is cell-membrane permeable, giving the ability to penetrate and act in surrounding cells. The effect of the ADC derives primarily from the released MAAA-1181a drug and to a lesser extent to the antibody-dependent cellular cytotoxic (ADCC) effector function of the conjugated antibody. The quality of MAAL-9001 antibody, MAAA-1162a drug-linker and the conjugated antibody is described in separate sections. The structures of DS-8201a, MAAA-1162a, MAAA-1181a, and MAAL-9001 are provided in Figure 1.

Full information for the active substance intermediate MAAA-1162a (C52H56FN9O13, MW 1034.05) was provided in the dossier. MAAA-1162a is composed of DX-8951·MsOH (drug intermediate) and MFAH (linker intermediate with maleimide functionality). The maleimide moiety reacts with the antibody (MAAL-9001) in the conjugation reaction to yield trastuzumab deruxtecan (DS-8201a). MAAA-1162a contains 3 stereogenic centres. General information was provided for solid state form, melting point, moisture sorption, UV-Vis absorption, optical rotation and solubility.

/////////////////////////////////////////////////////////////////////

str1
Flag Counter

AS ON DEC2021 3,491,869 VIEWS ON BLOG WORLDREACH AVAILABLEFOR YOUR ADVERTISEMENT

wdt-16

join me on Linkedin

Anthony Melvin Crasto Ph.D – India | LinkedIn

join me on Researchgate

RESEARCHGATE

This image has an empty alt attribute; its file name is research.jpg

join me on Facebook

Anthony Melvin Crasto Dr. | Facebook

join me on twitter

Anthony Melvin Crasto Dr. | twitter

+919321316780 call whatsaapp

EMAIL. amcrasto@amcrasto

/////////////////////////////////////////////////////////////////////////////

CLIP

Fam-trastuzumab deruxtecan-nxki is an ADC that is comprised of an anti-HER2 antibody and the potent topoisomerase inhibitor exatecan [206]. These two entities are connected via a liner consisting of a maleimide conjugation handle that includes a protease-cleavable Gly-Gly-Phe-Gly (GGFG) tetrapeptide linker. This conjugation handle could release deruxtecan after internalization of the conjugate by the cancer cells that recognize the antibody. Fam-trastuzumabderuxtecan-nxki was developed by Daiichi Sankyo and AstraZeneca, and granted approval by the FDA in December 2019 [207]. There are approximately eight payload molecules/antibodies. Fam-trastuzumab deruxtecan-nxki has been approved for the treatment of adult patients with HER2 positive breast cancer that is unresectable or metastatic [208]. The synthesis of GGFG linker is described in Scheme 38 [209,210]. First, commercial tert-butyl 2-aminoacetate 274 was treated with Fmoc-L-Phe-OH 275 in the presence of HOBt and DIC, giving the corresponding product 276. Further deprotection of Fmoc group and amide formation gave the intermediate 278, which then underwent removal of Fmoc group to give GGFG linker 279. Lastly, treatment of 279 with the activated ester 280 provided 281.

Preparation of the payload exatecan derivative is described in Scheme 39 [211]. Aluminum-catalyzed Friedel-Crafts acylation of o-fluorotoluene 282 with succinic andydride 283 gave intermediate 284 in 90% yield. Next, hydrogenation reduction ofthe carbonyl group of 284, followed by reaction with SOCl2 in MeOH, furnished 285, which then underwent nitration with H2SO4 and KNO3 to give compound 286 in 48% overall yield. Hydrolysis of 286 followed by treatment with polyphosphoric acid (PPA) gave the cyclization product 287 in only 27% yield. The transformation of 287 into 288 was realized following the four-step sequence: carbonyl reduction with NaBH4, acid-mediated elimination reaction, PtO2-catalyzed hydrogenation reduction, and acetylation with Ac2O. Regioselective benzylic oxidation of 288 in acetone with KMnO4 gave 289 in 65% yield, further functionalization with butyl nitrile and Zn-mediated acylation gave compound 290 in 66% yield over 2 steps. Treatment of 290 with aqueous HCl provided hydrolysis product 291 in 50% yield, which then coupled with ethyl trifluoroacetate to provide intermediate 292. Polycyclic compound 294 was prepared from 292 and 293 through a [4+2] cycloaddition reaction in refluxing toluene. The key intermediate 294 next underwent acidic hydrolysis and chiral resolution to provide the chiral product 295. Further condensation reaction with 296 in the presence of T3P and Et3N in DCM and TFA-promoted removal of the Boc group formed 297. The synthesis of fam-trastuzumab deruxtecan-nxki is described in Scheme 40 [212]. The linker 281 was coupled to 297 in the presence of T3P and Et3N to give the linker-payload 298. Through transformation of the disulfide bonds into free sulfhydryl groups for linkage (DTT in pH 8.0 buffer), followed by re-oxidation of the remaining disulfide bonds with cysteine, the linker-payload 298 was conjugated to the anti-HER2 mAb to give fam-trastuzumab deruxtecan-nxki (XXIX) based on the amount of protein with approximately eight linker/payloads per antibody.

[206] T.N. Iwata, K. Sugihara, T. Wada, T. Agatsuma, [Fam-] trastuzumab deruxtecan (DS-8201a)-induced antitumor immunity is facilitated by the anti-CTLA-4 antibody in a mouse model, PLoS One 14 (2019) 0222280.

[207] R. Voelker, Another targeted therapy for ERBB2-positive breast cancer, JAMA 323 (2020) 408.

[208] S. Modi, C. Saura, T. Yamashita, Y.H. Park, S.B. Kim, K. Tamura, F. Andre, H. Iwata, Y. Ito, J. Tsurutani, J. Sohn, N. Denduluri, C. Perrin, K. Aogi, E. Tokunaga, S.A. Im, K.S. Lee, S.A. Hurvitz, J. Cortes, C. Lee, S. Chen, L. Zhang, J. Shahidi, A. Yver, I. Krop, Trastuzumab deruxtecan in previously treated HER2-positive breast cancer, N. Engl. J. Med. 382 (2020) 610-621.

[209] C.L. Law, K. Klussman, A.F. Wahl, P. Senter, S. Doronina, B. Toki, Treatment of immunological disorders using anti-CD30 antibodies, 2003.WO2003043583.

[210] S. Doronina, P.D. Senter, B.E. Toki, Pentapeptide compounds and uses related thereto, 2002. WO2002088172. [211] H. Terasawa, A. Ejima, S. Ohsuki, K. Uoto, Hexa-cyclic compound, 1998. US5834476.

[212] G.M. Dubowchik, R.A. Firestone, L. Padilla, D. Willner, S.J. Hofstead, K. Mosure, J.O. Knipe, S.J. Lasch, P.A. Trail, Cathepsin B-labile dipeptide linkers for lysosomal release of doxorubicin from internalizing immunoconjugates: model studies of enzymatic drug release and antigen-specific in vitro anticancer activity, Bioconjugate. Chem 13 (2002) 855-869.

Monoclonal antibody
TypeWhole antibody
SourceHumanized
TargetHER2
Clinical data
Trade namesEnhertu
Other namesDS-8201a, fam-trastuzumab deruxtecan-nxki
AHFS/Drugs.comMonograph
License dataUS DailyMedTrastuzumab_deruxtecanUS FDAEnhertu
Pregnancy
category
AU: D[1]
Routes of
administration
Intravenous
ATC codeL01FD04 (WHO)
Legal status
Legal statusAU: S4 (Prescription only) [1]US: ℞-only [2]EU: Rx-only [3]Rx-only[4]
Identifiers
CAS Number1826843-81-5
PubChem SID384585505
DrugBankDB14962
UNII5384HK7574
KEGGD11529
ChEMBLChEMBL4297844
Chemical and physical data
FormulaC6460H9972N1724O2014S44.(C52H57F1N9O13)8

Medical uses

Trastuzumab deruxtecan-nxki is indicated for the treatment of adults with unresectable (unable to be removed with surgery) or metastatic (when cancer cells spread to other parts of the body) HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting and for adults with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen.[6][7]

Side effects and label warnings

The most common side effects are nausea, fatigue, vomiting, alopecia (hair loss), constipation, decreased appetite, anemia (hemoglobin in blood is below the reference range), decreased neutrophil count (white blood cells that help lead your body’s immune system response to fight infection), diarrhea, leukopenia (other white blood cells that help the immune system), cough and decreased platelet count (component of blood whose function is to react to bleeding from blood vessel injury by clumping, thereby initiating a blood clot).[6]

The prescribing information for fam-trastuzumab deruxtecan-nxki includes a boxed warning to advise health care professionals and patients about the risk of interstitial lung disease (a group of lung conditions that causes scarring of lung tissues) and embryo-fetal toxicity.[6] Interstitial lung disease and pneumonitis, including cases resulting in death, have been reported with fam-trastuzumab deruxtecan-nxki.[6]

History

The U.S. Food and Drug Administration (FDA) approved fam-trastuzumab deruxtecan-nxki in December 2019.[6][9] The application for fam-trastuzumab deruxtecan-nxki was granted accelerated approvalfast track designation, and breakthrough therapy designation.[6]

The FDA approved fam-trastuzumab deruxtecan-nxki based on the results of one clinical trial enrolling 184 female patients with HER2-positive, unresectable and/or metastatic breast cancer who had received two or more prior anti-HER2 therapies in the metastatic setting.[6] These patients were heavily pretreated in the metastatic setting, receiving between two and 17 therapies prior to receiving fam-trastuzumab deruxtecan-nxki.[6] Patients in the clinical trial received fam-trastuzumab deruxtecan-nxki every three weeks and tumor imaging was obtained every six weeks.[6] The overall response rate was 60.3%, which reflects the percentage of patients who had a certain amount of tumor shrinkage with a median duration of response of 14.8 months.[6]

The FDA granted the approval of Enhertu to Daiichi Sankyo.[6]

On 10 December 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a conditional marketing authorization for the medicinal product Enhertu, intended for the treatment of metastatic HER2-positive breast cancer.[10][11] Enhertu was reviewed under EMA’s accelerated assessment program. The applicant for this medicinal product is Daiichi Sankyo Europe GmbH. Trastuzumab deruxtecan was approved for medical use in the European Union in January 2021.[3][4]

In January 2021, the U.S. Food and Drug Administration (FDA) granted accelerated approval to fam-trastuzumab deruxtecan-nxki for the treatment of adults with locally advanced or metastatic HER2-positive gastric or gastroesophageal (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen.[7][12]

Efficacy was evaluated in a multicenter, open-label, randomized trial (DESTINY-Gastric01, NCT03329690) in participants with HER2-positive locally advanced or metastatic gastric or GEJ adenocarcinoma who had progressed on at least two prior regimens, including trastuzumab, a fluoropyrimidine- and a platinum-containing chemotherapy.[7] A total of 188 participants were randomized (2:1) to receive fam-trastuzumab deruxtecan-nxki 6.4 mg/kg intravenously every three weeks or physician’s choice of either irinotecan or paclitaxel monotherapy.[7]

References

  1. Jump up to:a b c “Enhertu”Therapeutic Goods Administration (TGA). 18 October 2021. Retrieved 22 October 2021.
  2. ^ “Enhertu- fam-trastuzumab deruxtecan-nxki injection, powder, lyophilized, for solution”DailyMed. Retrieved 15 January 2021.
  3. Jump up to:a b c “Enhertu EPAR”European Medicines Agency (EMA). 9 December 2020. Retrieved 31 March 2021.
  4. Jump up to:a b c “Enhertu approved in the EU for the treatment of HER2-positive metastatic breast cancer” (Press release). AstraZeneca. 20 January 2021. Retrieved 21 January 2021.
  5. ^ A HER2-Targeting Antibody–Drug Conjugate, Trastuzumab Deruxtecan (DS-8201a), Enhances Antitumor Immunity in a Mouse Model
  6. Jump up to:a b c d e f g h i j k l m n “FDA approves new treatment option for patients with HER2-positive breast cancer who have progressed on available therapies”U.S.Food and Drug Administration (FDA) (Press release). 20 December 2019. Archived from the original on 20 December 2019. Retrieved 20 December 2019. Public Domain This article incorporates text from this source, which is in the public domain.
  7. Jump up to:a b c d e f “FDA approves fam-trastuzumab deruxtecan-nxki for HER2-positive gastric adenocarcinomas”U.S. Food and Drug Administration (FDA). 15 January 2021. Retrieved 15 January 2021. Public Domain This article incorporates text from this source, which is in the public domain.
  8. ^ “Enhertu Approved in Japan for Treatment of Patients with HER2 Positive Unresectable or Metastatic Breast Cancer” (Press release). Daiichi Sankyo. 25 March 2020. Retrieved 21 January 2021 – via Business Wire.
  9. ^ “Drug Trials Snapshot: Enhertu”U.S. Food and Drug Administration (FDA). 20 December 2019. Retrieved 24 January 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  10. ^ “Enhertu: Pending EC decision”European Medicines Agency (EMA). 10 December 2020. Retrieved 11 December 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  11. ^ “Trastuzumab deruxtecan recommended for approval in the EU by CHMP for HER2-positive metastatic breast cancer” (Press release). AstraZeneca. 14 December 2020. Retrieved 21 January 2021.
  12. ^ “Enhertu approved in the US for the treatment of patients with previously treated HER2-positive advanced gastric cancer” (Press release). AstraZeneca. 18 January 2021. Retrieved 22 January 2021.

Further reading

////////////Fam-trastuzumab deruxtecan-nxki ,, FDA 2019, APROVALS 2019, DS-8201a

wdt-6

NEW DRUG APPROVALS

ONE TIME

$10.00

L-CARNOSINE


Carnosine.svg
ChemSpider 2D Image | L-Carnosine | C9H14N4O3

L-CARNOSINE

  • Molecular FormulaC9H14N4O3
  • Average mass226.232 Da

(2S)-2-(3-aminopropanamido)-3-(1H-imidazol-5-yl)propanoic acid
(E)-N-(3-Amino-1-hydroxypropylidene)-L-histidine [ACD/IUPAC Name] 
206-169-9[EINECS]305-84-0[RN]
8HO6PVN24Wカルノシン , Dragosine, Ignotin, Ignotine, Karnozin, L-Carnosine, N-(β-Alanyl)-L-histidine, NSC 524045, Sevitin, β-Alanylhistidine 
CarnosineCAS Registry Number: 305-84-0CAS Name: b-Alanyl-L-histidine 
Additional Names: ignotine 
Molecular Formula: C9H14N4O3, Molecular Weight: 226.23 
Percent Composition: C 47.78%, H 6.24%, N 24.77%, O 21.22% 
Literature References: Naturally occurring dipeptide found in large amounts in skeletal muscle. Also present in other tissues such as brain, cardiac muscle, kidney. Water soluble antioxidant; functions as a free-radical scavenger. Isoln: Gulewitsch, Amiradzibi, Ber.33, 1902 (1900); Wolff, Wilson, J. Biol. Chem.95, 495 (1932); 109, 565 (1935). Synthesis from histidine and b-iodo- or b-nitropropionyl chloride: Baumann, Ingvaldsen, ibid.35, 271 (1918); Barger, Tutin, Biochem. J.12, 406 (1918). Later syntheses: Sifford, du Vigneaud, J. Biol. Chem.108, 753 (1935); R. A. Turner, J. Am. Chem. Soc.75, 2388 (1953); F. J. Vinick, S. Jung, J. Org. Chem.48, 392 (1983). Crystal structure: H. Itoh et al.,Acta Crystallogr.33B, 2959 (1977). Possible role in wound healing: D. E. Fischer et al.,Proc. Soc. Exp. Biol. Med.158, 402 (1978). Review of physiological properties and therapeutic potential: S. E. Gariballa, A. J. Sinclair, Age Ageing29, 207-210 (2000). 
Properties: Crystals from aqueous ethanol, mp 262° (dec) (Vinick, Jung); also reported as mp 260° (capillary tube) and as mp 308-309° (Dennis bar) (Sifford, du Vigneaud). [a]D25 +21.0° (c = 1.5 in water). pK1 2.64; pK2 6.83; pK3 9.51. Alkaline reaction. One gram dissolves in 3.1 ml water at 25°. 
Melting point: mp 262° (dec) (Vinick, Jung); mp 260° (capillary tube) and as mp 308-309° (Dennis bar) (Sifford, du Vigneaud) 
pKa: pK1 2.64; pK2 6.83; pK3 9.51 
Optical Rotation: [a]D25 +21.0° (c = 1.5 in water) 
Derivative Type: Nitrate 
CAS Registry Number: 5852-98-2 
Molecular Formula: C9H15N5O6, Molecular Weight: 289.25 
Percent Composition: C 37.37%, H 5.23%, N 24.21%, O 33.19% 
Properties: Crystals, dec 222°. [a]D20 +24.1° (c = 1.5 in water). Very sol in water. 
Optical Rotation: [a]D20 +24.1° (c = 1.5 in water) 
Derivative Type: Hydrochloride 
CAS Registry Number: 5852-99-3 
Molecular Formula: C9H15ClN4O3, Molecular Weight: 262.69 
Percent Composition: C 41.15%, H 5.76%, Cl 13.50%, N 21.33%, O 18.27% 
Properties: Crystals, dec 245°. Very sol in water. 
Derivative Type: D-Form 
CAS Registry Number: 5853-00-9 
Properties: Crystals, mp 260°. [a]D28 -20.4° (c = 1.5). 
Melting point: mp 260° 
Optical Rotation: [a]D28 -20.4° (c = 1.5)

Carnosine (beta-alanyl-L-histidine) is a dipeptide molecule, made up of the amino acids beta-alanine and histidine. It is highly concentrated in muscle and brain tissues.[citation needed] Carnosine was discovered by Russian chemist Vladimir Gulevich.[2]

Carnosine is naturally produced by the body in the liver[3] from beta-alanine and histidine. Like carnitine, carnosine is composed of the root word carn, meaning “flesh”, alluding to its prevalence in meat.[4] There are no plant-based sources of carnosine,[5] however synthetic supplements do exist.

str1
Flag Counter

AS ON DEC2021 3,491,869 VIEWS ON BLOG WORLDREACH AVAILABLEFOR YOUR ADVERTISEMENT

SYN

WO2009033754 PAGE: 98 claimed protein

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2009033754

SYN

 US 4446149 A 1984 

 JP 02221230 A 1990

Showa Igakkai Zasshi 1974, V34(3), P271-83 

 Russian Journal of General Chemistry 2007, V77(9), P1576-1579 

 Chemische Berichte 1961, V94, P2768-78 

 Farmaco, Edizione Scientifica 1968, V23(9), P859-69

Paper

 Journal of the American Chemical Society 1953, V75, P2388-90 

+21.9 °

Conc: 3.0 g/100mL;water ; Wavlenght: 589.3 nm; Temp: 20 °C

 Annali di Chimica (Rome, Italy) 1968, V58(11), P1431-4 

DE 3540632 A1 1986 

 Z. physiol. Chem. 1914, V87, P1-11 

PAPER

Chemistry – A European Journal (2003), 9, (8), 1714-1723.

PAPER

Journal of Magnetic Resonance (2003), 164, (2), 256-269.

SYN

WO  2001064638

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2001064638

Example 1
(S) -2- (Cyanoacetylamino) -3- (l_ * H-imidazol-4-yl) propionic acid, sodium salt

To a solution of sodium ethoxide obtained by dissolving 5.57 g (0.24 mol) of sodium in 800 ml of ethanol was added 40.0 g (0.26 mol) of L-histidine at room temperature. After 15 minutes, 44.12 g (0.39 mol) of ethyl cyanoacetate were added and the suspension was refluxed for 16 hours. After cooling to room temperature, the mixture was filtered. The yellowish filtrate was concentrated in vacuo, the residue was slurried in ethyl acetate, filtered, washed with ethyl acetate and purified by flash chromatography on silica gel (eluent: gradient ethyl acetate → methanol / ethyl acetate 3: 1).
Yield: 28.42 g (46%)
1HNMR (DMSO- ^ 6, 00 MHz): δ = 8,28 (d, 1H); 7,45 (s, 1H); 6,7 (s, 1H); 5,5 (br. s, 1H); 4,12-4,20 (m, 1H); 3,65 (s, 2H); 2,95-3,05 (m, 1H); 2,8-2,9 (m, 1H).
13C NMR (DMSO- 6, 100 MHz): δ = 174,05; 161,09; 134,25; 131,97; 119,66; 116,43; 54,83; 29,13; 25,20.

Example 2
(• S) -2- (Cyanoacetylamino) -3- (1-δ-imidazol-4-yl) propionic acid, sodium salt

9.80 g of sodium hydride (60% in mineral oil) and 50.6 g
(0.51 mol) were added at room temperature to a suspension of 40.0 g (0.26 mol) of L-histidine in 750 ml of N, N-dimethylformamide Given methyl cyanoacetate. The mixture was heated to 155 ° C. for 2 h in an open flask and the solution thus obtained was analyzed by means of HPLC.
Histidine (8 area%) and (S) -2- (cyanoacetylamino) -3- (1H-imidazol-4-yl) propionic acid sodium salt (38 area%) were identified.

Example 3
(S) -2- (Cyanoacetylamino) -3- (l-ö r -imidazol-4-yl) propionic acid

To a solution of sodium ethoxide obtained by dissolving 4.02 g (0.175 mol) of sodium in 280 ml of ethanol, 28.27 g (0.18 mol) of L-Ηistidine were added at room temperature. The mixture was heated slowly and 30.92 g (0.27 mol) of ethyl cyanoacetate were added dropwise at a temperature of 60.degree. The mixture was heated further and the ethanol was distilled off, the amount of ethanol distilled off being continuously replaced in portions by N, N-dimethylformamide. At the end of the reaction, the temperature of the solution was 130 ° C. The mixture was stirred at this temperature for a further 2 hours. The brown reaction mixture (200 g) was cooled to 50 ° C. and 30 g of concentrated hydrochloric acid were metered in. About 70 g of solvent (Η 2O / N, N-dimethylformamide mixture) distilled off. The viscous suspension was mixed with 200 g of acetone, cooled to -10 ° C. and filtered. For recrystallization, the residue was dissolved in water and the pH was adjusted to 5.0. On cooling (<5 ° C.) a white solid precipitated out, which was filtered off, washed with ethanol and dried at 40 ° C./20 mbar.
Yield: 26.39 g (66%).
IR (KBr): v = 3421, 3240, 3149, 3059, 2970, 2255, 1653, 1551, 1396, 1107, 1088, 979, 965, 826, 786, 638 cm is “1 .
1HΝMR (DMSO-c 6 , 400 MHz): δ = 11.0 (br., 2H); 8.50 (d, 1H); 7.68 (s, 1H); 6.85 (s, 1H); 4.35-4.48 ( m, 1H); 3.68 (s, 2H); 2.92-3.03 (, 1H); 2.82-2.91 (m, 1H).

13 C NMR (DMSO- 6 , 100 MHz): δ = 172.23; 161.92; 134.55; 132.70; 116.73; 115.87; 52.80; 28.68; 25.06.
LC-MS: mlz = 223 ([M + H]), 205, 177, 156, 110.
The optical purity was determined to be> 99.8% on a sample obtained according to the above procedure. The determination was carried out by hydrolysis of the amide bond (6 N hydrochloric acid, 110 ° C., 24 h), followed by derivatization of the released histidine with trifluoroacetic anhydride and isobutyl chloroformate. A D-histidine content of <0.1% was detected by gas chromatography on a chiral stationary phase.

Example 4
L-Carnosine

To a solution of 1.90 g (7.8 mmol) of (<S) -2- (cyanoacetylamino) -3- (1H-imidazol-4-yl) propionic acid sodium salt (prepared according to Example 1) in 50 ml of ethanol / conc.
Ammonia solution (V: V- 4: 1) were given 0.3 g of rhodium / activated charcoal (5% Rh). The

The mixture was hydrogenated at 110 ° C. and 45 bar for 1 hour. The catalyst was then filtered off and the filtrate was adjusted to pH 8.2 with formic acid. After the solution had been concentrated in vacuo, the residue was suspended in 200 ml of ethanol and heated to 60 ° C. for 30 minutes. The product was filtered off, washed successively with ethanol, ethyl acetate and diethyl ether and finally dried.
Yield: 1.33 g (76%)
1H NMR (D 2 O, 400 MΗz): δ = 7.70 (s, 1Η); 6.93 (s, 1Η); 4.43-4.50 (m, 1Η); 3.20-3.28 (m, 2Η); 3.11-3.19 (m, 1H); 2.95-3.03 (m, 1H); 2.61-2.71 (m, 2H).
The optical purity was determined by the method described in Example 3 to be 99.5%.

Example 5
(S) -2- (Cyanoacetylamino) -3- (1-O-imidazol-4-yl) propionic acid methyl ester

To a solution of sodium methoxide obtained by dissolving 0.94 g (40.7 mmol; 1.95 equiv.) Of sodium in 100 ml of methanol, 5.0 g (20.4 mmol) were added at room temperature

L-histidine methyl ester dihydrochloride added. After 30 minutes, 3.03 g
(30.6 mmol) of methyl cyanoacetate were added and the mixture was left on for 16 hours

Boiled under reflux. After cooling to room temperature, the mixture was filtered.

The yellowish filtrate was concentrated in vacuo and the residue was purified by means of flash chromatography on silica gel (eluent: gradient ethyl acetate – »ethyl acetate / methanol 3: 1).
Yield: 1.51 g (31%)
1H MR (OMSO-de, 400 MHz): δ = 8.65 (d, 1H); 7.52 (s. 1H); 6.8 (s, 1H); 4.45 ^ 1.55 (m,

1H); 3,69 (s, 2H); 3,62 (s, 3H); 3,3 (br., 1H); 2,82-2,98 (m, 2H).

Example 6
L-Carnosine

1.76 g of Rh / C (0.4 mol% of pure Rh based on the starting material used) in a mixture of 94.2 g of ammonia solution (25% in H 2 O) and 62.8 g of methanol were placed in a 1 liter pressure autoclave . The autoclave was closed, the contents were heated to 90 ° C. and 40 bar hydrogen was injected. A solution of 20.0 g (0.09 mol) (* S) -2- (cyanoacetylamino) -3- (1H-imidazol-4-yl) propionic acid (prepared according to Example 3) was then within one hour Mixture 94.2 g ammonia solution (25% in Η 2O) and 62.8 g of methanol are metered in. After a one hour post-reaction at 90 ° C., the reaction mixture was cooled to room temperature. The pressure in the autoclave was released and the catalyst was filtered off over activated charcoal. An HPLC in-process analysis showed that the clear greenish reaction solution (326.2 g) contained 5.74% (m / m) carnosine, which corresponds to a selectivity of 92% with complete conversion. The reaction mixture was then concentrated to approx. 60 g on a rotary evaporator. As a result of the dropwise addition of 174 g of ethanol, a white solid precipitated out, which was filtered off and dried at 50 ° C./20 mbar.

Ausbeute: 13,0 g (64%)
1H NMR (D2O, 400 MHz): δ = 7,70 (s, 1H); 6,93 (s, 1H); 4,43-4,50 (m, 1H); 3,20-3,28 (m, 2H); 3,11-3,19 (m, 1H); 2,95-3,03 (m, 1H); 2,61-2,71 (m, 2H).
I3C NMR (D20, 100 MHz): δ = 178,58; 172,39; 136,46; 133,90; 118,37; 55,99; 36,65; 33,09; 29,74.
LC-MS: m/z = 227 ([M+H]+), 210, 192, 164, 146, 136, 110.

Example 7
L-Carnosine

In a 1 liter pressure autoclave, a solution of 10.00 g (45.0 mmol) (S) -2- (cyanoacetylamino) -3 was added to 0.88 g of Rh / C (0.4 mol% of pure Rh based on the starting material used) – (1H-imidazol-4-yl) propionic acid (prepared according to Example 3) in a mixture of 157 g conc. NΗ 3/ Methanol (m / m = 3: 2) was added. The autoclave was closed and flushed twice with 40 bar nitrogen and once with hydrogen. The mixture was heated to 90 ° C. and 40 bar hydrogen was injected. After 3 h at 90 ° C., the reaction mixture was cooled to room temperature, the autoclave was depressurized and the catalyst was separated off by filtration. An in-process analysis (HPLC) showed that the reaction solution (147.2 g) contained 6.38% (m / m) carnosine, which corresponds to a selectivity of 92% when the conversion is complete. The reaction mixture was then concentrated to 41.2 g on a rotary evaporator. 124 g of ethanol were added dropwise at room temperature and the flask was placed in a refrigerator overnight. The next day the precipitate was filtered off, washed with ethanol and dried in a drying cabinet at 40 ° C./20 mbar. 7.96 g (78%) of a slightly greenish solid with a content (HPLC) of 98.0% (m / m) were obtained.

Example 8
L-Carnosine

The procedure was as described in Example 7, with the difference that 5% Rh on aluminum oxide was used as the catalyst. Under these conditions, L-carnosine was formed with 83% selectivity.

Example 9
L-Carnosine

4.5 g of Raney cobalt (doped with 0.3% iron) in 195 g of methanol were placed in a 1 liter pressure autoclave. A solution of 30.0 g (0.135 mol) (S) -2- (cyanoacetylamino) -3- (1H-imidazol-4-yl) propionic acid (prepared according to Example 3) in 375 g ammonia solution (25% in Η O) was admitted. The autoclave was closed and flushed twice with 40 bar nitrogen. Then 45 bar of hydrogen were injected and the contents were heated to 100 ° C. within half an hour. After an after-reaction of 3 hours at 100 ° C., the reaction mixture was cooled to room temperature and the pressure in the autoclave was released. An HPLC in-process analysis showed that the reaction solution (590.8 g) contained 4.68% (mim) carnosine, which corresponds to a selectivity of 91% with complete conversion.

Example 10
L-Carnosine

In a 100 ml
pressure autoclave were to a solution of 2.0 g (9.0 mmol) (ιS) -2- (cyanoacetylamino) -3- (lH-imidazol-4-yl) propionic acid (prepared according to Example 3) in a Mixture of 25 g of ammonia solution (25% in Η 2 O) and 13 g of methanol, 1.1 g of Raney nickel (doped with 1.8% molybdenum) were added. The autoclave was closed and placed in an oil bath preheated to 100.degree. After 10 minutes, 50 bar of hydrogen were injected. After 2.5 hours at 100 ° C., the reaction mixture was
cooled to room temperature and the pressure on the autoclave was released. An HPLC in-process analysis showed that the reaction solution (39.4 g) contained 4.54% (m / m) carnosine, which, with a conversion of 99%, corresponds to a selectivity of 89%.

Example 11
L-Carnosine

In a 1 liter pressure autoclave, 4.50 g of Raney cobalt (doped with 0.3% iron) in a mixture of 285 g of conc. Ammonia / methanol (mim = 1.9: 1) submitted. The autoclave was closed and flushed twice with 40 bar nitrogen. Then 45 bar of hydrogen were injected and the mixture was heated to 100.degree. A solution of 30.0 g (0.135 mol) of (S) -2- (cyanoacetylamino) -3- (1H-imidazol-4-yl) propionic acid (prepared according to Example 3) in a mixture of 285 g was then obtained within one hour conc. Ammonia / methanol (m / m = 1.9: 1) metered in. After a one hour post-reaction at 100 ° C., the reaction mixture was cooled to room temperature. The pressure in the autoclave was released and the catalyst was filtered off. A ΗPLC in-process analysis showed that the reddish brown reaction solution (310.5 g) contained 9.57% (m / m) carnosine,

Example 12
(S) -2- (Cyanoacetylamino) -3- (3-methyl-3-ö r -imidazol-4-yl) propionic acid, sodium salt

0.50 g (2.95 mmol) of 3-methyl-L-histidine were added at 40 ° C. to a solution of 0.20 g (2.94 mmol) of sodium ethoxide in 5.60 g of ethanol. The clear solution was heated to 60 ° C. and 0.50 g (4.43 mmol) ethyl cyanoacetate was added dropwise. The mixture was refluxed for 1 hour. Then 10 mg (0.15 mmol) of imidazole were added. The ethanol was then slowly distilled off and the amount of ethanol distilled off was continuously replaced in portions by N, N-dimethylformamide. After a subsequent reaction time of 2 h at 125 ° C., the reaction mixture was carefully concentrated and the residue was purified by means of flash column chromatography on silica gel (eluent: gradient ethyl acetate → ethyl acetate / methanol 2: 1). 0.49 g (64%) of a slightly yellowish solid were obtained.

DC: Rf = 0,46 (Ethanol/H2O 3:7).
1H NMR (DMSO-öfe, 400 MHz): δ = 7,91 (d, 1H); 7,38 (s, 1H); 6,58 (s, 1H); 3,97 (q, 1H);

3,68 (s, 2H); 3,50 (s, 3H); 3,01 (dd, 1H); 2,85 (dd, 1H).
13C NMR (DMSO-^6, 100 MHz): δ = 171,54; 160,80; 136,95; 128,68; 126,91; 116,40;

54,26; 30,65; 25,97; 25,11.
LC-MS: m/z = 237 ([M+H]+), 219, 193, 191, 176, 166, 164, 150, 109.

Example 13
(S) -2- (3-aminopropionylamino) -3- (3-methyl-3Jϊ-imidazol-4-yl) propionic acid
(= anserine)

To a solution of 0.20 g (0.77 mmol) (5) -2- (cyanoacetylamino) -3- (3-methyl-3H-imidazol-4-yl) propionic acid sodium salt (prepared according to Example 12) in 2 , 4 g of methanol and 1.6 g of ammonia solution (25% in Η 2 O), 16 mg of rhodium / Al 2 O 3 (5% Rh) were added. The mixture was hydrogenated at 85 ° C. and 50 bar for 1 hour. The catalyst was then filtered off. Anserine could be clearly detected in the filtrate by means of thin-layer chromatography, HPLC (by co-injection with a commercial reference substance) and LC-MS.
Gross yield: approx. 45%.
TLC: R f = 0.25 (ethyl acetate / methanol / Ammom  ak H 2 O 43: 35: 8: 10).
LC-MS: m / z = 241 ([M + H] +), 224, 206, 180, 170, 126, 109.

SYN

Synthesis of L-carnosine from two amino acids β -alanine-amide and L-histidine 

Synthesis of L-carnosine from two amino acids β -alanine-amide and L-histidine

SYN

https://pubs.rsc.org/en/content/articlelanding/2019/cy/c9cy01622h

L-Carnosine (L-Car, β-alanyl-L-histidine) is a bioactive dipeptide with important physiological functions. Direct coupling of unprotected β-Ala (β-alanine) with L-His (L-histidine) mediated by an enzyme is a promising method for L-Car synthesis. In this study, a new recombinant dipeptidase (SmPepD) from Serratia marcescens with a high synthetic activity toward L-Car was identified by a genome mining approach and successfully expressed in Escherichia coli. Divalent metal ions strongly promoted the synthetic activity of SmPepD, with up to 21.7-fold increase of activity in the presence of 0.1 mM MnCl2. Higher temperature, lower pH and increasing substrate loadings facilitated the L-Car synthesis. Pilot biocatalytic syntheses of L-Car were performed comparatively in batch and continuous modes. In the continuous process, an ultra-filtration membrane reactor with a working volume of 5 L was employed for catalyst retention. The dipeptidase, SmPepD, showed excellent operational stability without a significant decrease in space–time yield after 4 days. The specific yield of L-Car achieved was 105 gCar gcatalyst−1 by the continuous process and 30.1 gCar gcatalyst−1 by the batch process. A nanofiltration membrane was used to isolate the desired product L-Car from the reaction mixture by selectively removing the excess substrates, β-Ala and L-His. As a result, the final L-Car content was effectively enriched from 2.3% to above 95%, which gave L-Car in 99% purity after ethanol precipitation with a total yield of 60.2%. The recovered substrate mixture of β-Ala and L-His can be easily reused, which will enable the economically attractive and environmentally benign production of the dipeptide L-Car.

Graphical abstract: A green-by-design bioprocess for l-carnosine production integrating enzymatic synthesis with membrane separation

SYNhttps://patents.google.com/patent/US20170211105A1/en

  • Carnosine is a dipeptide of the amino acids beta-alanine and histidine. It is highly concentrated in muscle and brain tissues.
  • [0005]
    β-Alanine (or beta-alanine) is a naturally occurring beta amino acid, which is an amino acid in which the amino group is at the β-position from the carboxylate group (i.e., two atoms away).
  • [0006]
    β-Alanine is not used in the biosynthesis of any major proteins or enzymes. It is formed in vivo by the degradation of dihydrouracil and carnosine. It is a component of the naturally occurring peptides carnosine and anserine and also of pantothenic acid (vitamin B5), which itself is a component of coenzyme A. Under normal conditions, β-alanine is metabolized into acetic acid.
  • [0007]
    β-Alanine is the rate-limiting precursor of carnosine, which is to say carnosine levels are limited by the amount of available β-alanine, not histidine. Supplementation with β-alanine has been shown to increase the concentration of carnosine in muscles, decrease fatigue in athletes and increase total muscular work done.
  • [0008]
    Carnosine and beta-alanine are popular dietary supplements currently produced using chemical methods. Beta-alanine is also a synthetic precursor to pantothenic acid, the essential vitamin B5. Beta-alanine can also be used as a monomer for the production of a polymeric resin (U.S. Pat. No. 4,082,730).
  • [0009]
    Naturally, carnosine is produced exclusively in animals from beta-alanine (via uracil) and histidine. In yeasts and animals, beta-alanine is typically produced by degradation of uracil. Chemically, carnosine can be synthesized from histidine and beta-alanine derivatives. For example, the coupling of an N-(thiocarboxy) anhydride of beta-alanine with histidine has been described (Vinick et al. A simple and efficient synthesis of L-carnosine. J. Org. Chem, 1983, 48(3), pp. 392-393).
  • [0010]
    Beta-alanine can be produced synthetically by Michael addition of ammonia to ethyl- or methyl-acrylate. This requires the use of the caustic agent ammonia and high pressures. It is also natively produced in bacteria and yeasts in small quantities. In bacteria, beta-alanine is produced by decarboxylation of aspartate. Lysates of bacteria have been used in biocatalytic production from aspartate (Patent CN104531796A).
  • [0011]
    There remains a need in the industry for a safer, more economical system for the production of carnosine and beta-alanine.
  • [0105]
    The present disclosure provides methods for the biosynthetic production of beta-alanine and carnosine using engineered microorganisms of the present invention.
  • [0106]
    In one embodiment, a method of producing beta-alanine is provided. The method comprises providing a fermentation media comprising a carbon substrate, contacting said media with a recombinant yeast microorganism expressing an engineered beta-alanine biosynthetic pathway wherein said pathway comprises an aspartate to beta-alanine conversion (pathway step a), and culturing the yeast in conditions whereby beta-alanine is produced.
  • [0107]
    In another embodiment of the present invention, a method of producing carnosine is provided. The method comprises providing a fermentation media comprising a carbon substrate, contacting said media with a recombinant yeast microorganism expressing an engineered carnosine biosynthetic pathway wherein said pathway comprises (i) an aspartate to beta-alanine conversion (pathway step a) and (ii) a beta-alanine to carnosine conversion (pathway step b), and culturing the yeast in conditions whereby carnosine is produced.
  • [0108]
    In another embodiment of the present invention, a method of producing carnosine via biotransformation is provided. The method comprises providing a media comprising a carbon substrate and exogenously added beta-alanine, contacting said media with a recombinant yeast microorganism expressing an engineered carnosine biosynthetic pathway wherein said pathway comprises (i) a beta-alanine to carnosine conversion (pathway step b), and culturing the yeast in conditions whereby carnosine is produced.
  • [0109]
    Some embodiments of the present invention comprise yeast strains designated ca1 and ca2 and are derived from S. cerevisiae strain S288C. Each encodes at least 2 foreign genes under inducible Gal promoters. Strain ca1 also contains an additional gene, panM. The specific proteins encoded by each strain and their sequences, source, and accession numbers are provided in Table 1. The genes for these proteins are synthesized with yeast-optimized codon usage, assembled into singular genetic cassettes, and then inserted into the HO locus of S288C under URA2 selection. Strains ca1 and ca2 served as parent strains to derivatives comprising various heterologous genes. Ca2 served as a parent strain for ca7, ca8, ca9, ca10, ca11, ca12, ca14, ca15 in which the carnosine synthase is a different ortholog. Strain ca1 served as the parent strain to strains ca19, ca20, ca21, ca22, ca23, ca24, ca27, and ca28 in which the aspartate decarboxylase is a different ortholog. The specific proteins encoded by each strain and their sequences, source, and accession numbers are provided in Table 2.
  • [0110]
    Aspartate, histidine, and the cofactors involved in the carnosine and beta-alanine pathway are universal to all organisms, and thus the host organism could be any genetically tractable organism (plants, animals, bacteria, or fungi). Amongst yeasts, other species such as S. pombe or P. pastoris are plausible alternatives. Within the S. cerevisiae species, other strains more amenable to large-scale productions, such as CENPalpha, may be utilized.
  • [0111]
    The Gal promoter used in embodiments of the present invention could be replaced with constitutive promoters, or other chemically-inducible, growth phase-dependent, or stress-induced promoters. Heterologous genes of the present invention may be genomically encoded or alternatively encoded on plasmids or yeast artificial chromosomes (YACs). All genes introduced could be encoded with alternate codon usage without altering the biochemical composition of the system. All enzymes used in embodiments of the present invention have extensive orthologs in the biosphere that could be encoded as alternatives.
  • [0112]
    Aspartate, histidine, and the cofactors involved in this pathway are universal to all organisms, and thus the host organism could be any genetically tractable organism (plants, animals, bacteria, or fungi). Among yeast, other species such as S. pombe or P. pastoris are plausible alternatives. Within the S. cerevisiae species, other strains more amenable to large scale productions, such as CENPalpha, may be preferable. The panD gene can replaced with orthologs from other bacteria. Examples include Corynebacterium glutamicum Escherichia coli, Helicobacter pylori, Tribolium castaneum, Pectobacterium carotovorum, Actinoplanes sp. SE50/110, Taoultella ornithinolytica, Methanocaldococcus jannaschii DSM 2661 and Methanocaldococcus bathoardescens. This is shown in Table 2. Carnosine synthase is natively found in mammals, birds, and reptiles. Therefore, the chicken enzyme used in ca1 and ca2 could be replaced by various orthologs. Examples include Gorilla gorilla, Falco perefrinus, Allpiucator mississsippiensis, Ailuoropoda melanoleuca, Ursus maritimus, Python bivittatus, and Orcinus orca. This is shown in Table 2.

Culture Conditions

  • [0113]
    The growth medium used to test for production of carnosine by the engineered strains was Teknova SC Minimal Broth with Raffinose supplemented with 1% galactose.
  • [0114]
    A variety of purification protocols including solid phase extraction and cation exchange chromatography may be employed to purify the desired products from the culture supernatant or the yeast cell pellet fraction.

SYN

https://pdfs.semanticscholar.org/4dc4/f6e93a62e630429c7830f117ab2564e124a2.pdf?_ga=2.190125161.395277661.1640054641-1458054132.1640054641

str1
str2
Names
Preferred IUPAC name(2S)-2-(3-Aminopropanamido)-3-(3H-imidazol-4-yl)propanoic acid
Other namesβ-Alanyl-L-histidine
Identifiers
CAS Number305-84-0 
3D model (JSmol)Interactive imageInteractive image
ChEBICHEBI:15727 
ChEMBLChEMBL242948 
ChemSpider388363 
ECHA InfoCard100.005.610 
IUPHAR/BPS4559
KEGGC00386 
PubChem CID439224
UNII8HO6PVN24W 
CompTox Dashboard (EPA)DTXSID80879594 
showInChI
showSMILES
Properties
Chemical formulaC9H14N4O3
Molar mass226.236 g·mol−1
AppearanceCrystalline solid
Melting point253 °C (487 °F; 526 K) (decomposition)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
check verify (what is  ?)
Infobox references
wdt-16

join me on Linkedin

Anthony Melvin Crasto Ph.D – India | LinkedIn

join me on Researchgate

RESEARCHGATE

This image has an empty alt attribute; its file name is research.jpg

join me on Facebook

Anthony Melvin Crasto Dr. | Facebook

join me on twitter

Anthony Melvin Crasto Dr. | twitter

+919321316780 call whatsaapp

EMAIL. amcrasto@amcrasto

/////////////////////////////////////////////////////////////////////////////

Biosynthesis

Carnosine is synthesized within the body from beta-alanine and histidine. Beta-alanine is a product of pyrimidine catabolism[6] and histidine is an essential amino acid. Since beta-alanine is the limiting substrate, supplementing just beta-alanine effectively increases the intramuscular concentration of carnosine.[7][8]

Physiological effects

pH buffer

Carnosine has a pKa value of 6.83, making it a good buffer for the pH range of animal muscles.[9] Since beta-alanine is not incorporated into proteins, carnosine can be stored at relatively high concentrations (millimolar). Occurring at 17–25 mmol/kg (dry muscle),[10] carnosine (β-alanyl-L-histidine) is an important intramuscular buffer, constituting 10-20% of the total buffering capacity in type I and II muscle fibres.

Anti-oxidant

Carnosine has been proven to scavenge reactive oxygen species (ROS) as well as alpha-beta unsaturated aldehydes formed from peroxidation of cell membrane fatty acids during oxidative stress. It also buffers pH in muscle cells, and acts as a neurotransmitter in the brain. It is also a zwitterion, a neutral molecule with a positive and negative end.[citation needed]

Antiglycating

Carnosine acts as an antiglycating agent, reducing the rate of formation of advanced glycation end-products (substances that can be a factor in the development or worsening of many degenerative diseases, such as diabetesatherosclerosischronic kidney failure, and Alzheimer’s disease[11]), and ultimately reducing development of atherosclerotic plaque build-up.[12][13][14]

Geroprotective

Carnosine is considered as a geroprotector.[15] Carnosine can increase the Hayflick limit in human fibroblasts,[16] as well as appearing to reduce the telomere shortening rate.[17] Carnosine may also slow aging through its anti-glycating properties (chronic glycolysis is speculated to accelerate aging).[18]

Other

Carnosine can chelate divalent metal ions.[12]

Carnosine administration has been shown to have cardioprotective properties, protecting against ischaemia-reperfusion injury, and doxorubicin-induced cardiomyopathy.[19]

Carnosine demonstrated neuroprotective effects in multiple animal studies.[20][21][22]

Research has demonstrated a positive association between muscle tissue carnosine concentration and exercise performance.[23][24][25] β-Alanine supplementation is thought to increase exercise performance by promoting carnosine production in muscle. Exercise has conversely been found to increase muscle carnosine concentrations, and muscle carnosine content is higher in athletes engaging in anaerobic exercise.[23]

Carnosine appears to protect in experimental ischemic stroke by influencing a number of mechanisms that are activated during stroke. It is a potent pH buffer and has anti matrix metalloproteinase activity, antioxidant and antiexcitotoxic properties and protects the blood brain barrier [26], [27], [28], [29], [30], [31], [32]. [33], [34], [35].

References

  1. ^ “C9625 L-Carnosine ~99%, crystalline”Sigma-Aldrich.
  2. ^ Gulewitsch, Wl.; Amiradžibi, S. (1900). “Ueber das Carnosin, eine neue organische Base des Fleischextractes”Berichte der Deutschen Chemischen Gesellschaft33 (2): 1902–1903. doi:10.1002/cber.19000330275.
  3. ^ Trexler, Eric T.; Smith-Ryan, Abbie E.; Stout, Jeffrey R.; Hoffman, Jay R.; Wilborn, Colin D.; Sale, Craig; Kreider, Richard B.; Jäger, Ralf; Earnest, Conrad P.; Bannock, Laurent; Campbell, Bill (2015-07-15). “International society of sports nutrition position stand: Beta-Alanine”Journal of the International Society of Sports Nutrition12: 30. doi:10.1186/s12970-015-0090-yISSN 1550-2783PMC 4501114PMID 26175657.
  4. ^ Hipkiss, A. R. (2006). “Does chronic glycolysis accelerate aging? Could this explain how dietary restriction works?”. Annals of the New York Academy of Sciences1067 (1): 361–8. Bibcode:2006NYASA1067..361Hdoi:10.1196/annals.1354.051PMID 16804012S2CID 41175541.
  5. ^ Alan R. Hipkiss (2009). “Chapter 3: Carnosine and Its Possible Roles in Nutrition and Health”. Advances in Food and Nutrition Research.
  6. ^ “beta-ureidopropionate + H2O => beta-alanine + NH4+ + CO2”reactome. Retrieved 2020-02-08. Cytosolic 3-ureidopropionase catalyzes the reaction of 3-ureidopropionate and water to form beta-alanine, CO2, and NH3 (van Kuilenberg et al. 2004).
  7. ^ Derave W, Ozdemir MS, Harris R, Pottier A, Reyngoudt H, Koppo K, Wise JA, Achten E (August 9, 2007). “Beta-alanine supplementation augments muscle carnosine content and attenuates fatigue during repeated isokinetic contraction bouts in trained sprinters”. J Appl Physiol103 (5): 1736–43. doi:10.1152/japplphysiol.00397.2007PMID 17690198S2CID 6990201.
  8. ^ Hill CA, Harris RC, Kim HJ, Harris BD, Sale C, Boobis LH, Kim CK, Wise JA (2007). “Influence of beta-alanine supplementation on skeletal muscle carnosine concentrations and high intensity cycling capacity”. Amino Acids32 (2): 225–33. doi:10.1007/s00726-006-0364-4PMID 16868650S2CID 23988054.
  9. ^ Bate-Smith, EC (1938). “The buffering of muscle in rigor: protein, phosphate and carnosine”Journal of Physiology92 (3): 336–343. doi:10.1113/jphysiol.1938.sp003605PMC 1395289PMID 16994977.
  10. ^ Mannion, AF; Jakeman, PM; Dunnett, M; Harris, RC; Willan, PLT (1992). “Carnosine and anserine concentrations in the quadriceps femoris muscle of healthy humans”. Eur. J. Appl. Physiol64 (1): 47–50. doi:10.1007/BF00376439PMID 1735411S2CID 24590951.
  11. ^ Vistoli, G; De Maddis, D; Cipak, A; Zarkovic, N; Carini, M; Aldini, G (Aug 2013). “Advanced glycoxidation and lipoxidation end products (AGEs and ALEs): an overview of their mechanisms of formation”Free Radic. Res47: Suppl 1:3–27. doi:10.3109/10715762.2013.815348PMID 23767955S2CID 207517855.
  12. Jump up to:a b Reddy, V. P.; Garrett, MR; Perry, G; Smith, MA (2005). “Carnosine: A Versatile Antioxidant and Antiglycating Agent”. Science of Aging Knowledge Environment2005 (18): pe12. doi:10.1126/sageke.2005.18.pe12PMID 15872311.
  13. ^ Rashid, Imran; Van Reyk, David M.; Davies, Michael J. (2007). “Carnosine and its constituents inhibit glycation of low-density lipoproteins that promotes foam cell formation in vitro”. FEBS Letters581 (5): 1067–70. doi:10.1016/j.febslet.2007.01.082PMID 17316626S2CID 46535145.
  14. ^ Hipkiss, A. R. (2005). “Glycation, ageing and carnosine: Are carnivorous diets beneficial?”. Mechanisms of Ageing and Development126 (10): 1034–9. doi:10.1016/j.mad.2005.05.002PMID 15955546S2CID 19979631.
  15. ^ Boldyrev, A. A.; Stvolinsky, S. L.; Fedorova, T. N.; Suslina, Z. A. (2010). “Carnosine as a natural antioxidant and geroprotector: From molecular mechanisms to clinical trials”. Rejuvenation Research13 (2–3): 156–8. doi:10.1089/rej.2009.0923PMID 20017611.
  16. ^ McFarland, G; Holliday, R (1994). “Retardation of the Senescence of Cultured Human Diploid Fibroblasts by Carnosine”. Experimental Cell Research212 (2): 167–75. doi:10.1006/excr.1994.1132PMID 8187813.
  17. ^ Shao, Lan; Li, Qing-Huan; Tan, Zheng (2004). “L-Carnosine reduces telomere damage and shortening rate in cultured normal fibroblasts”. Biochemical and Biophysical Research Communications324 (2): 931–6. doi:10.1016/j.bbrc.2004.09.136PMID 15474517.
  18. ^ Hipkiss, A. R. (2006). “Does Chronic Glycolysis Accelerate Aging? Could This Explain How Dietary Restriction Works?”. Annals of the New York Academy of Sciences1067 (1): 361–8. Bibcode:2006NYASA1067..361Hdoi:10.1196/annals.1354.051PMID 16804012S2CID 41175541.
  19. ^ McCarty, Mark F; DiNicolantonio, James J (2014-08-04). “β-Alanine and orotate as supplements for cardiac protection”Open Heart1 (1): e000119. doi:10.1136/openhrt-2014-000119ISSN 2053-3624PMC 4189254PMID 25332822.
  20. ^ Virdi, Jasleen Kaur; Bhanot, Amritansh; Jaggi, Amteshwar Singh; Agarwal, Neha (2020-10-02). “Investigation on beneficial role of l -carnosine in neuroprotective mechanism of ischemic postconditioning in mice: possible role of histidine histamine pathway”International Journal of Neuroscience130 (10): 983–998. doi:10.1080/00207454.2020.1715393ISSN 0020-7454PMID 31951767S2CID 210710039.
  21. ^ Rajanikant, G.K.; Zemke, Daniel; Senut, Marie-Claude; Frenkel, Mark B.; Chen, Alex F.; Gupta, Rishi; Majid, Arshad (November 2007). “Carnosine Is Neuroprotective Against Permanent Focal Cerebral Ischemia in Mice”Stroke38 (11): 3023–3031. doi:10.1161/STROKEAHA.107.488502ISSN 0039-2499PMID 17916766.
  22. ^ Min, Jiangyong; Senut, Marie-Claude; Rajanikant, Krishnamurthy; Greenberg, Eric; Bandagi, Ram; Zemke, Daniel; Mousa, Ahmad; Kassab, Mounzer; Farooq, Muhammad U.; Gupta, Rishi; Majid, Arshad (October 2008). “Differential neuroprotective effects of carnosine, anserine, and N -acetyl carnosine against permanent focal ischemia”Journal of Neuroscience Research86 (13): 2984–2991. doi:10.1002/jnr.21744PMC 2805719PMID 18543335.
  23. Jump up to:a b Culbertson, Julie Y.; Kreider, Richard B.; Greenwood, Mike; Cooke, Matthew (2010-01-25). “Effects of Beta-Alanine on Muscle Carnosine and Exercise Performance:A Review of the Current Literature”Nutrients2 (1): 75–98. doi:10.3390/nu2010075ISSN 2072-6643PMC 3257613PMID 22253993.
  24. ^ Baguet, Audrey; Bourgois, Jan; Vanhee, Lander; Achten, Eric; Derave, Wim (2010-07-29). “Important role of muscle carnosine in rowing performance”Journal of Applied Physiology109 (4): 1096–1101. doi:10.1152/japplphysiol.00141.2010ISSN 8750-7587PMID 20671038.
  25. ^ Varanoske, Alyssa N.; Hoffman, Jay R.; Church, David D.; Wang, Ran; Baker, Kayla M.; Dodd, Sarah J.; Coker, Nicholas A.; Oliveira, Leonardo P.; Dawson, Virgil L.; Fukuda, David H.; Stout, Jeffrey R. (2017-09-07). “Influence of Skeletal Muscle Carnosine Content on Fatigue during Repeated Resistance Exercise in Recreationally Active Women”Nutrients9 (9): 988. doi:10.3390/nu9090988ISSN 2072-6643PMC 5622748PMID 28880219.
showvtePeptidesneuropeptides

26. Kim EH, Kim ES, Shin D, Kim D, Choi S, Shin YJ, Kim KA, Noh D, Caglayan AB, Rajanikant GK, Majid A, Bae ON. Carnosine Protects against Cerebral Ischemic Injury by Inhibiting Matrix-Metalloproteinases. Int J Mol Sci. 2021 Jul 13;22(14):7495. doi: 10.3390/ijms22147495. PMID: 34299128; PMCID: PMC8306548.

27. Jain S, Kim ES, Kim D, Burrows D, De Felice M, Kim M, Baek SH, Ali A, Redgrave J, Doeppner TR, Gardner I, Bae ON, Majid A. Comparative Cerebroprotective Potential of d- and l-Carnosine Following Ischemic Stroke in Mice. Int J Mol Sci. 2020 Apr 26;21(9):3053. doi: 10.3390/ijms21093053. PMID: 32357505; PMCID: PMC7246848.

28. Kim ES, Kim D, Nyberg S, Poma A, Cecchin D, Jain SA, Kim KA, Shin YJ, Kim EH, Kim M, Baek SH, Kim JK, Doeppner TR, Ali A, Redgrave J, Battaglia G, Majid A, Bae ON. LRP-1 functionalized polymersomes enhance the efficacy of carnosine in experimental stroke. Sci Rep. 2020 Jan 20;10(1):699. doi: 10.1038/s41598-020-57685-5. PMID: 31959846; PMCID: PMC6971073.

29. Schön M, Mousa A, Berk M, Chia WL, Ukropec J, Majid A, Ukropcová B, de Courten B. The Potential of Carnosine in Brain-Related Disorders: A Comprehensive Review of Current Evidence. Nutrients. 2019 May 28;11(6):1196. doi: 10.3390/nu11061196. PMID: 31141890; PMCID: PMC6627134.

30. Davis CK, Laud PJ, Bahor Z, Rajanikant GK, Majid A. Systematic review and stratified meta-analysis of the efficacy of carnosine in animal models of ischemic stroke. J Cereb Blood Flow Metab. 2016 Oct;36(10):1686-1694. doi: 10.1177/0271678X16658302. Epub 2016 Jul 8. PMID: 27401803; PMCID: PMC5046161.

31. Baek SH, Noh AR, Kim KA, Akram M, Shin YJ, Kim ES, Yu SW, Majid A, Bae ON. Modulation of mitochondrial function and autophagy mediates carnosine neuroprotection against ischemic brain damage. Stroke. 2014 Aug;45(8):2438-2443. doi: 10.1161/STROKEAHA.114.005183. Epub 2014 Jun 17. PMID: 24938837; PMCID: PMC4211270.

32. Bae ON, Majid A. Role of histidine/histamine in carnosine-induced neuroprotection during ischemic brain damage. Brain Res. 2013 Aug 21;1527:246-54. doi: 10.1016/j.brainres.2013.07.004. Epub 2013 Jul 11. PMID: 23850642.

33. Bae ON, Serfozo K, Baek SH, Lee KY, Dorrance A, Rumbeiha W, Fitzgerald SD, Farooq MU, Naravelta B, Bhatt A, Majid A. Safety and efficacy evaluation of carnosine, an endogenous neuroprotective agent for ischemic stroke. Stroke. 2013 Jan;44(1):205-12. doi: 10.1161/STROKEAHA.112.673954. Epub 2012 Dec 18. PMID: 23250994; PMCID: PMC3678096.

34. Min J, Senut MC, Rajanikant K, Greenberg E, Bandagi R, Zemke D, Mousa A, Kassab M, Farooq MU, Gupta R, Majid A. Differential neuroprotective effects of carnosine, anserine, and N-acetyl carnosine against permanent focal ischemia. J Neurosci Res. 2008 Oct;86(13):2984-91. doi: 10.1002/jnr.21744. PMID: 18543335; PMCID: PMC2805719.

35. Rajanikant GK, Zemke D, Senut MC, Frenkel MB, Chen AF, Gupta R, Majid A. Carnosine is neuroprotective against permanent focal cerebral ischemia in mice. Stroke. 2007 Nov;38(11):3023-31. doi: 10.1161/STROKEAHA.107.488502. Epub 2007 Oct 4. PMID: 17916766.

////////L-CARNOSINE, カルノシン , b-Alanyl-L-histidine, ignotine, 8HO6PVN24W, カルノシン , Dragosine, Ignotin, Ignotine, Karnozin, L-Carnosine, N-(β-Alanyl)-L-histidine, NSC 524045, Sevitin, β-Alanylhistidine

wdt-17

NEW DRUG APPROVALS

one time

$10.00

ALLOPURINOL


Allopurinol V.1.svg
ChemSpider 2D Image | Allopurinol | C5H4N4O

ALLUPURINOL

  • Molecular FormulaC5H4N4O
  • Average mass136.111 Da
  • аллопуринол [Russian]ألوبيرينول [Arabic]别嘌醇 [Chinese]

1H-Pyrazolo(3,4-d)pyrimidin-4-ol
2,5-Dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one
206-250-9[EINECS]315-30-0[RN]
4H-Pyrazolo[3,4-d]pyrimidin-4-one, 1,5-dihydro-, radical ion(1+)
4H-Pyrazolo[3,4-d]pyrimidin-4-one, 1,7-dihydro-
691008-24-9[RN]
7H-Pyrazolo[3,4-d]pyrimidin-4-ol

Allopurinol is a medication used to decrease high blood uric acid levels.[2] It is specifically used to prevent gout, prevent specific types of kidney stones and for the high uric acid levels that can occur with chemotherapy.[3][4] It is taken by mouth or injected into a vein.[4]

Common side effects when used by mouth include itchiness and rash.[4] Common side effects when used by injection include vomiting and kidney problems.[4] While not recommended historically, starting allopurinol during an attack of gout appears to be safe.[5][6] In those already on the medication, it should be continued even during an acute gout attack.[5][3] While use during pregnancy does not appear to result in harm, this use has not been well studied.[1] Allopurinol is in the xanthine oxidase inhibitor family of medications.[4]

Allopurinol was approved for medical use in the United States in 1966.[4] It is on the World Health Organization’s List of Essential Medicines, the safest and most effective medicines needed in a health system.[7] Allopurinol is available as a generic medication.[4] In 2019, it was the 43rd most commonly prescribed medication in the United States, with more than 15 million prescriptions.[8][9]

ALLUPRINOLCAS Registry Number: 315-30-0 
CAS Name: 1,5-Dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one 
Additional Names: 1H-pyrazolo[3,4-d]pyrimidin-4-ol; 4-hydroxypyrazolo[3,4-d]pyrimidine; HPP 
Manufacturers’ Codes: BW-56158 
Trademarks: Adenock (Mitsubishi); Allurit (Aventis); Aloral (Lagap); Alositol (Tanabe); Allo-Puren (Isis); Allozym (Sawai); Allural (Rovi); Anoprolin (Azwell); Anzief (Nippon Chemiphar); Apulonga (Dorsch); Apurol (Siegfried); Apurin (GEA); Bleminol (Gepepharm); Caplenal (Teva); Cellidrin (Hennig); Cosuric (DDSA); Dabroson (Hoyer); Embarin (Merckle); Epidropal (Teofarma); Foligan (DESMA); Gichtex (Gerot); Hamarin (Roche); Hexanurat (Durascan); Ketanrift (Ohta); Lopurin (Abbott); Lysuron (Roche); Miniplanor (Galen); Monarch (SS Pharm.); Remid (TAD); Riball (Schering AG); Sigapurol (Siegfried); Suspendol (Merckle); Takanarumin (Takata); Uricemil (Molteni); Uripurinol (Azupharma); Urosin (Roche); Urtias (Novartis); Zyloprim (GSK); Zyloric (GSK) 
Molecular Formula: C5H4N4O, Molecular Weight: 136.11 
Percent Composition: C 44.12%, H 2.96%, N 41.16%, O 11.75% 
Literature References: Xanthine oxidase inhibitor; decreases uric acid production. Prepn: Robins, J. Am. Chem. Soc.78, 784 (1956); Schmidt, Druey, Helv. Chim. Acta39, 986 (1956); Druey, Schmidt, US2868803 (1959 to Ciba); GB798646 (1958 to Wellcome Found.); Hitchings, Falco, US3474098 (1969 to Burroughs Wellcome). Physiological and biochemical studies: Hitchings, in Biochem. Aspects Antimetab. Drug Hydroxylation, D. Shugar, Ed. (Academic Press, London, 1969) pp 11-22, C.A.75, 3531h (1971). Clinical trial in treatment of renal calculi: M. J. V. Smith, J. Urol.117, 690 (1977); B. Ettinger et al.,N. Engl. J. Med.315, 1386 (1986). Use in hyperuricemia and gout: G. R. Boss, J. E. Seegmiller, ibid.300, 1459 (1977). Effect on renal function in treatment of gout: T. Gibson, Ann. Rheum. Dis.41, 59 (1982). Comprehensive description: S. A. Benezra, T. R. Bennett, Anal. Profiles Drug Subs.7, 1-17 (1978). 
Properties: Crystals, mp above 350°. uv max (0.1N NaOH): 257 nm (e 7200); (0.1N HCl): 250 nm (e 7600); (methanol): 252 nm (e 7600). Soly in mg/ml at 25°: water 0.48; n-octanol <0.01; chloroform 0.60; ethanol 0.30; DMSO 4.6. pKa 10.2. 
Melting point: mp above 350° 
pKa: pKa 10.2 
Absorption maximum: uv max (0.1N NaOH): 257 nm (e 7200); (0.1N HCl): 250 nm (e 7600); (methanol): 252 nm (e 7600) 
Derivative Type: Sodium salt 
CAS Registry Number: 17795-21-0 
Trademarks: Aloprim (Nabi) 
Molecular Formula: C5H3N4NaO, Molecular Weight: 158.09Percent Composition: C 37.99%, H 1.91%, N 35.44%, Na 14.54%, O 10.12% 
Properties: White amorphous mass. pKa 9.31. 
pKa: pKa 9.31 
Therap-Cat: Treatment of hyperuricemia and chronic gout. Antiurolithic. 
Keywords: Antigout; Antiurolithic; Xanthine Oxidase Inhibitor.

Synthesis ReferenceDruey, J. and Schmidt, P.; US. Patent 2868,803; January 13,1959; assigned to Ciba Pharmaceutical Products Inc. Hitchings, G.H. and Falco, EA.; U.S. Patent 3,474,098; October 21,1969; assigned to Bur- roughs Wellcome & Co. Cresswell, R.M.and Mentha, J.W.; US.Patent4,146,713; March27,1979; assigned to Bur- roughs Wellcome & Co.
SYN 

str1
Flag Counter

AS ON DEC2021 3,491,869 VIEWS ON BLOG WORLDREACH AVAILABLEFOR YOUR ADVERTISEMENT

SYN

File:Allopurinol synthesis.svg

http://drugsynthesis.blogspot.co.uk/2011/11/laboratory-synthesis-of-allopurinol.html

Reference(s):

  1. US 2 868 803 (Ciba; 13.1.1959; CH-prior. 10.2.1956).
  2. DAS 1 720 024 (Wellcome Found; appl. 12.7.1967; GB-prior. 14.7.1966).

Similar process:

  1. DAS 1 904 894 (Wellcome Found; appl. 31.1.1969; GB-prior. 2.2.1968).
  2. US 4 146 713 (Burroughs Wellcome; 27.3.1979; GB-prior. 2.2.1968).

Alternative syntheses:

  1. US 3 474 098 (Burroughs Wellcome; 21.10.1969; prior. 29.3.1956).
  2. DAS 2 224 382 (Henning Berlin; appl. 18.5.1972).
  3. DE 1 118 221 (Wellcome Found; appl. 4.8.1956; GB-prior. 10.8.1955).
  4. DAS 1 814 082 (Wellcome Found; appl. 11.12.1968).
  5. DAS 1 950 075 (Henning Berlin; appl. 3.10.1969).

SYNCondensation of hydrazine with ethoxymethylenemalononitrile (I) leads to 3-amino-4-cyanopyrazole (II), which, by hydrolysis with sulphuric acid, gives the corresponding amide (III); heating III with formamide in excess results in allopurinol (IV). The synthesis of allopurinol can be illustrated as below: 

SYN

Synthesis

IR

https://www.sciencedirect.com/science/article/abs/pii/S0099542808600878

Infrared Spectrum The infrared spectrum of allopurinol is shown in Figure 1 . in KBr with a Perkin Elmer model 457 infrared spectrophotometer. with the structure of allopurinol . It was taken as a 0.2% dispersion of allopurinol Table I gives the infrareg assignments consistent Table I Infrared Spectral Assignments for Allopurinol Frequency (cm-l) Assignment

3060 CH stretching vibrations of the pyrimidine ring

1700 CO stretching vibration of the keto form of the 4-hydroxy tautomer 1

590 ring vibrations

1245 CH in-plane deformation

NMR

1 H-NMR Spectra of Allopurinol standard
Clinical data
Trade namesZyloprim, Caplenal, Zyloric, others
AHFS/Drugs.comMonograph
MedlinePlusa682673
License dataUS DailyMedAllopurinol
Pregnancy
category
AU: B2[1]
Routes of
administration
By mouth (tablet), intravenous
ATC codeM04AA01 (WHO)
Legal status
Legal statusAU: S4 (Prescription only)UK: POM (Prescription only)US: ℞-only
Pharmacokinetic data
Bioavailability78±20%
Protein bindingNegligible
Metabolismliver (80% oxipurinol, 10% allopurinol ribosides)
Elimination half-life2 h (oxipurinol 18–30 h)
Identifiers
showIUPAC name
CAS Number315-30-0 
PubChem CID135401907
IUPHAR/BPS6795
DrugBankDB00437 
ChemSpider2010 
UNII63CZ7GJN5I
KEGGD00224 
ChEBICHEBI:40279 
ChEMBLChEMBL1467 
CompTox Dashboard (EPA)DTXSID4022573 
ECHA InfoCard100.005.684 
Chemical and physical data
FormulaC5H4N4O
Molar mass136.114 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI
  (verify)
wdt-16

join me on Linkedin

Anthony Melvin Crasto Ph.D – India | LinkedIn

join me on Researchgate

RESEARCHGATE

This image has an empty alt attribute; its file name is research.jpg

join me on Facebook

Anthony Melvin Crasto Dr. | Facebook

join me on twitter

Anthony Melvin Crasto Dr. | twitter

+919321316780 call whatsaapp

EMAIL. amcrasto@amcrasto

/////////////////////////////////////////////////////////////////////////////

Medical uses

Gout

Allopurinol is used to reduce urate formation in conditions where urate deposition has already occurred or is predictable. The specific diseases and conditions where it is used include gouty arthritis, skin tophi, kidney stones, idiopathic gout; uric acid lithiasis; acute uric acid nephropathy; neoplastic disease and myeloproliferative disease with high cell turnover rates, in which high urate levels occur either spontaneously, or after cytotoxic therapy; certain enzyme disorders which lead to overproduction of urate, for example: hypoxanthine-guanine phosphoribosyltransferase, including Lesch–Nyhan syndromeglucose 6-phosphatase including glycogen storage diseasephosphoribosyl pyrophosphate synthetasephosphoribosyl pyrophosphate amidotransferaseadenine phosphoribosyltransferase.

It is also used to treat kidney stones caused by deficient activity of adenine phosphoribosyltransferase.

Tumor lysis syndrome

Allopurinol was also commonly used to treat tumor lysis syndrome in chemotherapeutic treatments, as these regimens can rapidly produce severe acute hyperuricemia;[10] however, it has gradually been replaced by urate oxidase therapy.[11] Intravenous formulations are used in this indication when people cannot take medicine by mouth.[12]

Inflammatory bowel disease

Allopurinol cotherapy is used to improve outcomes for people with inflammatory bowel disease and Crohn’s disease who do not respond to thiopurine monotherapy.[13][14] Cotherapy has also been shown to greatly improve hepatoxicity side effects in treatment of IBD.[15] Cotherapy invariably requires dose reduction of the thiopurine, usually to one-third of the standard dose depending upon the patient’s genetic status for thiopurine methyltransferase.[16]

Psychiatric disorders

Allopurinol has been tested as an augmentation strategy for the treatment of mania in bipolar disorder. Meta-analytic evidence showed that adjunctive allopurinol was superior to placebo for acute mania (both with and without mixed features).[17] Its efficacy was not influenced by dosage, follow-up duration, or concurrent standard treatment.[17]

Side effects

Because allopurinol is not a uricosuric, it can be used in people with poor kidney function. However, for people with impaired kidney function, allopurinol has two disadvantages. First, its dosing is complex.[18] Second, some people are hypersensitive to the drug; therefore, its use requires careful monitoring.[19][20]

Allopurinol has rare but potentially fatal adverse effects involving the skin. The most serious adverse effect is a hypersensitivity syndrome consisting of fever, skin rash, eosinophiliahepatitis, and worsened renal function, collectively referred to as DRESS syndrome.[19] Allopurinol is one of the drugs commonly known to cause Stevens–Johnson syndrome and toxic epidermal necrolysis, two life-threatening dermatological conditions.[19] More common is a less-serious rash that leads to discontinuing this drug.[19]

More rarely, allopurinol can also result in the depression of bone marrow elements, leading to cytopenias, as well as aplastic anemia. Moreover, allopurinol can also cause peripheral neuritis in some patients, although this is a rare side effect. Another side effect of allopurinol is interstitial nephritis.[21]

Allopurinol should not be given to people who are allergic to it.[10]

Drug interactions

Drug interactions are extensive, and are as follows:[10]

  • Azathioprine and 6-mercaptopurine: Azathioprine is metabolised to 6-mercaptopurine which in turn is inactivated by the action of xanthine oxidase – the target of allopurinol. Giving allopurinol with either of these drugs at their normal dose will lead to overdose of either drug; only one-quarter of the usual dose of 6-mercaptopurine or azathioprine should be given;
  • Didanosine: plasma didanosine Cmax and AUC values were approximately doubled with concomitant allopurinol treatment; it should not be co-administered with allopuroinol and if it must be, the dose of should be reduced and the person should be closely monitored.

Allopurinol may also increase the activity or half-life of the following drugs, in order of seriousness and certainty of the interaction:[10]

Co-administration of the following drugs may make allopurinol less active or decrease its half-life:[10]

Co-administration of the following drugs may cause hypersensitivity or skin rash:[10]

Pharmacology

A common misconception is that allopurinol is metabolized by its target, xanthine oxidase, but this action is principally carried out by aldehyde oxidase.[22] The active metabolite of allopurinol is oxipurinol, which is also an inhibitor of xanthine oxidase. Allopurinol is almost completely metabolized to oxipurinol within two hours of oral administration, whereas oxipurinol is slowly excreted by the kidneys over 18–30 hours. For this reason, oxipurinol is believed responsible for the majority of allopurinol’s effect.[23]

Mechanism of action

Allopurinol is a purine analog; it is a structural isomer of hypoxanthine (a naturally occurring purine in the body) and is an inhibitor of the enzyme xanthine oxidase.[2] Xanthine oxidase is responsible for the successive oxidation of hypoxanthine and xanthine, resulting in the production of uric acid, the product of human purine metabolism.[2] In addition to blocking uric acid production, inhibition of xanthine oxidase causes an increase in hypoxanthine and xanthine. While xanthine cannot be converted to purine ribotides, hypoxanthine can be salvaged to the purine ribotides adenosine and guanosine monophosphates. Increased levels of these ribotides may cause feedback inhibition of amidophosphoribosyl transferase, the first and rate-limiting enzyme of purine biosynthesis. Allopurinol, therefore, decreases uric acid formation and may also inhibit purine synthesis.[24]

Pharmacogenetics

The HLA-B*5801 allele is a genetic marker for allopurinol-induced severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).[25][26] The frequency of the HLA-B*5801 allele varies between ethnicities: Han Chinese and Thai populations have HLA-B*5801 allele frequencies of around 8%, as compared to European and Japanese populations, who have allele frequencies of around 1.0% and 0.5%, respectively.[27] The increase in risk for developing allopurinol-induced SJS or TEN in individuals with the HLA-B*5801 allele (as compared to those who do not have this allele) is very high, ranging from a 40-fold to a 580-fold increase in risk, depending on ethnicity.[25][26] As of 2011 the FDA-approved drug label for allopurinol did not contain any information regarding the HLA-B*5801 allele, though FDA scientists did publish a study in 2011 which reported a strong, reproducible and consistent association between the allele and allopurinol-induced SJS and TEN.[28] However, the American College of Rheumatology recommends screening for HLA-B*5801 in high-risk populations (e.g. Koreans with stage 3 or worse chronic kidney disease and those of Han Chinese and Thai descent), and prescribing patients who are positive for the allele an alternative drug.[29] The Clinical Pharmacogenetics Implementation Consortium guidelines state that allopurinol is contraindicated in known carriers of the HLA-B*5801 allele.[30][31]

History

Allopurinol was first synthesized and reported in 1956 by Roland K. Robins (1926-1992), in a search for antineoplastic agents.[2][32] Because allopurinol inhibits the breakdown (catabolism) of the thiopurine drug mercaptopurine, and it was later tested by Wayne Rundles, in collaboration with Gertrude Elion‘s lab at Wellcome Research Laboratories to see if it could improve treatment of acute lymphoblastic leukemia by enhancing the action of mercaptopurine.[2][33] However, no improvement in leukemia response was noted with mercaptopurine-allopurinol co-therapy, so that work turned to other compounds and the team then started testing allopurinol as a potential for gout.[34] Allopurinol was first marketed as a treatment for gout in 1966.[33]

Society and culture

Pure allopurinol is a white powder.

Formulations

Allopurinol is sold as an injection for intravenous use[12] and as a tablet.[10]

Brands

Allopurinol has been marketed in the United States since 19 August 1966, when it was first approved by FDA under the trade name Zyloprim.[35] Allopurinol was marketed at the time by Burroughs-Wellcome. Allopurinol is a generic drug sold under a variety of brand names, including Allohexal, Allosig, Milurit, Alloril, Progout, Ürikoliz, Zyloprim, Zyloric, Zyrik, and Aluron.[36]

See also

References

  1. Jump up to:a b “Allopurinol Use During Pregnancy”Drugs.comArchived from the original on 20 August 2016. Retrieved 20 December 2016.
  2. Jump up to:a b c d e Pacher P, Nivorozhkin A, Szabó C (March 2006). “Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol”Pharmacological Reviews58 (1): 87–114. doi:10.1124/pr.58.1.6PMC 2233605PMID 16507884.
  3. Jump up to:a b World Health Organization (2009). Stuart MC, Kouimtzi M, Hill SR (eds.). WHO Model Formulary 2008. World Health Organization. p. 39. hdl:10665/44053ISBN 9789241547659.
  4. Jump up to:a b c d e f g “Allopurinol”. The American Society of Health-System Pharmacists. Archived from the original on 29 April 2016. Retrieved 8 December 2016.
  5. Jump up to:a b Robinson PC, Stamp LK (May 2016). “The management of gout: Much has changed”. Australian Family Physician45 (5): 299–302. PMID 27166465.
  6. ^ Satpanich, P; Pongsittisak, W; Manavathongchai, S (18 August 2021). “Early versus Late Allopurinol Initiation in Acute Gout Flare (ELAG): a randomized controlled trial”. Clinical Rheumatologydoi:10.1007/s10067-021-05872-8PMID 34406530S2CID 237156638.
  7. ^ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  8. ^ “The Top 300 of 2019”ClinCalc. Retrieved 16 October 2021.
  9. ^ “Allopurinol – Drug Usage Statistics”ClinCalc. Retrieved 16 October 2021.
  10. Jump up to:a b c d e f g “300 mg Allopurinol tables”UK Electronic Medicines Compendium. 7 April 2016. Archived from the original on 11 September 2016.
  11. ^ Jeha S (October 2001). “Tumor lysis syndrome”. Seminars in Hematology38 (4 Suppl 10): 4–8. doi:10.1016/S0037-1963(01)90037-XPMID 11694945.
  12. Jump up to:a b “Label for injectable Allopurinol”DailyMed. June 2014. Archived from the original on 13 September 2016.
  13. ^ Bradford K, Shih DQ (October 2011). “Optimizing 6-mercaptopurine and azathioprine therapy in the management of inflammatory bowel disease”World Journal of Gastroenterology17 (37): 4166–73. doi:10.3748/wjg.v17.i37.4166PMC 3208360PMID 22072847.
  14. ^ Sparrow MP, Hande SA, Friedman S, Cao D, Hanauer SB (February 2007). “Effect of allopurinol on clinical outcomes in inflammatory bowel disease nonresponders to azathioprine or 6-mercaptopurine”. Clinical Gastroenterology and Hepatology5 (2): 209–14. doi:10.1016/j.cgh.2006.11.020PMID 17296529.
  15. ^ Ansari A, Patel N, Sanderson J, O’Donohue J, Duley JA, Florin TH (March 2010). “Low-dose azathioprine or mercaptopurine in combination with allopurinol can bypass many adverse drug reactions in patients with inflammatory bowel disease”Alimentary Pharmacology & Therapeutics31 (6): 640–7. doi:10.1111/j.1365-2036.2009.04221.xPMID 20015102S2CID 6000856.
  16. ^ Ansari AR, Duley JA (March 2012). “Azathioprine co-therapy with allopurinol for inflammatory bowel disease: trials and tribulations” (PDF). Rev Assoc Med Bras58 (Suppl.1): S28–33.
  17. Jump up to:a b Bartoli F, Cavaleri D, Bachi B, Moretti F, Riboldi I, Crocamo C, Carrà G (September 2021). “Repurposed drugs as adjunctive treatments for mania and bipolar depression: A meta-review and critical appraisal of meta-analyses of randomized placebo-controlled trials”. Journal of Psychiatric Research143: 230–238. doi:10.1016/j.jpsychires.2021.09.018PMID 34509090S2CID 237485915.
  18. ^ Dalbeth N, Stamp L (2007). “Allopurinol dosing in renal impairment: walking the tightrope between adequate urate lowering and adverse events”. Seminars in Dialysis20 (5): 391–5. doi:10.1111/j.1525-139X.2007.00270.xPMID 17897242S2CID 1150852.
  19. Jump up to:a b c d Chung WH, Wang CW, Dao RL (July 2016). “Severe cutaneous adverse drug reactions”. The Journal of Dermatology43 (7): 758–66. doi:10.1111/1346-8138.13430PMID 27154258S2CID 45524211.
  20. ^ Tsai TF, Yeh TY (2010). “Allopurinol in dermatology”. American Journal of Clinical Dermatology11 (4): 225–32. doi:10.2165/11533190-000000000-00000PMID 20509717S2CID 36847530.
  21. ^ De Broe ME, Bennett WM, Porter GA (2003). Clinical Nephrotoxins: Renal Injury from Drugs and ChemicalsSpringer Science+Business MediaISBN 9781402012778Acute interstitial nephritis has also been reported associated with by the administration of allopurinol.
  22. ^ Reiter S, Simmonds HA, Zöllner N, Braun SL, Knedel M (March 1990). “Demonstration of a combined deficiency of xanthine oxidase and aldehyde oxidase in xanthinuric patients not forming oxipurinol”. Clinica Chimica Acta; International Journal of Clinical Chemistry187 (3): 221–34. doi:10.1016/0009-8981(90)90107-4PMID 2323062.
  23. ^ Day RO, Graham GG, Hicks M, McLachlan AJ, Stocker SL, Williams KM (2007). “Clinical pharmacokinetics and pharmacodynamics of allopurinol and oxypurinol”. Clinical Pharmacokinetics46 (8): 623–44. doi:10.2165/00003088-200746080-00001PMID 17655371S2CID 20369375.
  24. ^ Cameron JS, Moro F, Simmonds HA (February 1993). “Gout, uric acid and purine metabolism in paediatric nephrology”. Pediatric Nephrology7 (1): 105–18. doi:10.1007/BF00861588PMID 8439471S2CID 34815040.
  25. Jump up to:a b “Uric Acid-Lowering Drugs Pathway, Pharmacodynamics”PharmGKB. Archived from the original on 8 August 2014.
  26. Jump up to:a b “PharmGKB”Archived from the original on 8 August 2014. Retrieved 1 August 2014.
  27. ^ “Allele Frequency Net Database”. Archived from the original on 28 August 2009.
  28. ^ Zineh I, Mummaneni P, Lyndly J, Amur S, La Grenade LA, Chang SH, et al. (December 2011). “Allopurinol pharmacogenetics: assessment of potential clinical usefulness”Pharmacogenomics12 (12): 1741–9. doi:10.2217/pgs.11.131PMID 22118056.
  29. ^ Khanna D, Fitzgerald JD, Khanna PP, Bae S, Singh MK, Neogi T, et al. (October 2012). “2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia”Arthritis Care & Research64 (10): 1431–46. doi:10.1002/acr.21772PMC 3683400PMID 23024028.
  30. ^ “Annotation of CPIC Guideline for allopurinol and HLA-B”PharmGKBArchived from the original on 8 August 2014. Retrieved 1 August 2014.
  31. ^ Hershfield MS, Callaghan JT, Tassaneeyakul W, Mushiroda T, Thorn CF, Klein TE, Lee MT (February 2013). “Clinical Pharmacogenetics Implementation Consortium guidelines for human leukocyte antigen-B genotype and allopurinol dosing”Clinical Pharmacology and Therapeutics93 (2): 153–8. doi:10.1038/clpt.2012.209PMC 3564416PMID 23232549.
  32. ^ Robins RK (1956). “Potential Purine Antagonists. I. Synthesis of Some 4,6-Substituted Pyrazolo \3,4-d] pyrimidines1”. J. Am. Chem. Soc78 (4): 784–790. doi:10.1021/ja01585a023.
  33. Jump up to:a b Sneader W (2005). Drug Discovery: A History. John Wiley & Sons. p. 254. ISBN 9780471899792.
  34. ^ Elion GB (April 1989). “The purine path to chemotherapy”. Science244 (4900): 41–7. Bibcode:1989Sci…244…41Edoi:10.1126/science.2649979PMID 2649979.
  35. ^ “FDA Approved Drug Products”Drugs@FDAArchived from the original on 14 August 2012. Retrieved 8 November 2013.
  36. ^ “Search Results for Allopurinol”DailyMedArchived from the original on 25 March 2012. Retrieved 27 July 2011.

Further reading

/////////////////////ALLUPURINOL, BW-56158, аллопуринол , ألوبيرينول , 别嘌醇 , 

NEW DRUG APPROVALS

ONE TIME

$10.00

XL 114, AUR 104 and XL 102, AUR 102 (NO CONCLUSIONS, ONLY PREDICTIONS)


File:Animated-Flag-India.gif - Wikimedia Commons
XL 102

XL 114

FOR BOTH, JUST PREDICTION

PREDICTIONS

or

front page image
Figure imgf000002_0001
Figure imgf000024_0001

N[C@@H](CO)c1nc(on1)[C@@H](NC(=O)N[C@H](C(=O)O)C(C)O)CC(N)=O

(2S)-2-[[(1S)-3-Amino-1-[3-[(1R)-1-amino-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl]-3-oxopropyl]carbamoylamino]-3-hydroxybutanoic acid.png
SVG Image

(2S)-2-[[(1S)-3-amino-1-[3-[(1R)-1-amino-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl]-3-oxopropyl]carbamoylamino]-3-hydroxybutanoic acid

CAS 2305027-62-5

C12 H20 N6 O7, 360.32Threonine, N-[[[(1S)-3-amino-1-[3-[(1R)-1-amino-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl]-3-oxopropyl]amino]carbonyl]-, (2S,3ξ)-N[C@@H](CO)c1nc(on1)[C@@H](NC(=O)N[C@H](C(=O)O)C(C)O)CC(N)=O

ALSO SEE

Figure imgf000003_0002
str1
(2S,3R)-2-[[(1S)-3-Amino-1-[3-[(1R)-1-amino-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl]-3-oxopropyl]carbamoylamino]-3-hydroxybutanoic acid.png

1673534-76-3C12 H20 N6 O7, 360.32
L-Threonine, N-[[[(1S)-3-amino-1-[3-[(1R)-1-amino-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl]-3-oxopropyl]amino]
(2S,3R)-2-[[(1S)-3-amino-1-[3-[(1R)-1-amino-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl]-3-oxopropyl]carbamoylamino]-3-hydroxybutanoic acidN-[[[(1S)-3-Amino-1-[3-[(1R)-1-amino-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl]-3-oxopropyl]amino]carbonyl]-L-threonine

CAS 1673534-76-3

PD-1-IN-1 free base, EX-A1918, CS-6240NSC-799645CA-170 (AUPM-170)|PDL1 inhibitorHY-101093, PD-1-IN-1

N[C@@H](CO)c1nc(on1)[C@@H](NC(=O)N[C@H](C(=O)O)[C@@H](C)O)CC(N)=O

XL 114, AUR 104

A novel covalent inhibitor of FABP5 for cancer therapy

XL 102,  AUR 102

A potent, selective and orally bioavailable inhibitor of cyclin-dependent kinase 7 (CDK7)

NO CONCLUSIONS, ONLY PREDICTIONS

PREDICTIONS MORE

(2R,3R)-2-[[(1S)-3-Amino-1-[3-[(1R)-1-amino-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl]-3-oxopropyl]carbamoylamino]-3-hydroxybutanoic acid.png
SVG Image

(2R,3R)-2-[[(1S)-3-amino-1-[3-[(1R)-1-amino-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl]-3-oxopropyl]carbamoylamino]-3-hydroxybutanoic acid

C12H20N6O7, 360.32

(2S,3S)-2-[[(1S)-3-Amino-1-[3-[(1S)-1-amino-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl]-3-oxopropyl]carbamoylamino]-3-hydroxybutanoic acid.png
SVG Image

(2S,3S)-2-[[(1S)-3-amino-1-[3-[(1S)-1-amino-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl]-3-oxopropyl]carbamoylamino]-3-hydroxybutanoic acid

XL102, AUR 102

XL102 is a potent, selective and orally bioavailable covalent inhibitor of CDK7, which is an important regulator of the cellular transcriptional and cell cycle machinery. CDK7 helps regulate cell cycle progression, with overexpression observed in multiple cancers, such as breast, prostate and ovarian cancers. In preclinical studies, XL102 revealed potent anti-proliferative activity, induced cell death in a large panel of cancer cell lines and caused tumor growth inhibition and regression in xenograft models, demonstrating its potential as a targeted antitumor agent.

In late 2020, Exelixis exercised its option to in-license XL102 (formerly AUR102) from Aurigene per the companies’ July 2019 collaboration, option and license agreement. Exelixis has assumed responsibility for the future clinical development, manufacturing and commercialization of XL102. Aurigene retains limited development and commercial rights for India and Russia.

SYN

ABOUT Fatty acid-binding proteins (FABPs)

Fatty acid-binding proteins (FABPs) are involved in binding and storing hydrophobic ligands such as long-chain fatty acids, as well as transporting them to the appropriate compartments in the cell. Epidermal fatty acid-binding protein (FABP5) is an intracellular lipid-binding protein that is abundantly expressed in adipocytes and macrophages. Previous studies have revealed that the FABP5 expression level is closely related to malignancy in various types of cancer. However, its precise functions in the metabolisms of cancer cells remain unclear. Here, we revealed that FABP5 knockdown significantly induced downregulation of the genes expression, such as hormone-sensitive lipase (HSL), monoacylglycerol lipase (MAGL), elongation of long-chain fatty acid member 6 (Elovl6), and acyl-CoA synthetase long-chain family member 1 (ACSL1), which are involved in altered lipid metabolism, lipolysis, and de novo FA synthesis in highly aggressive prostate and breast cancer cells. Moreover, we demonstrated that FABP5 induced inflammation and cytokine production through the nuclear factor-kappa B signaling pathway activated by reactive oxygen species and protein kinase C in PC-3 and MDA-MB-231 cells. Thus, FABP5 might regulate lipid quality and/or quantity to promote aggressiveness such as cell growth, invasiveness, survival, and inflammation in prostate and breast cancer cells. In the present study, we have revealed for the first time that high expression of FABP5 plays a critical role in alterations of lipid metabolism, leading to cancer development and metastasis in highly aggressive prostate and breast cancer cells.

Fatty acid-binding protein, epidermal is a protein that in humans is encoded by the FABP5 gene

Function

This gene encodes the fatty acid binding protein found in epidermal cells, and was first identified as being upregulated in psoriasis tissue. Fatty acid binding proteins are a family of small, highly conserved, cytoplasmic proteins that bind long-chain fatty acids and other hydrophobic ligands. It is thought that FABPs roles include fatty acid uptake, transport, and metabolism.[6]

The phytocannabinoids (THC and CBD) inhibit endocannabinoid anandamide (AEA) uptake by targeting FABP5, and competition for FABPs may in part or wholly explain the increased circulating levels of endocannabinoids reported after consumption of cannabinoids.[7] Results show that cannabinoids inhibit keratinocyte proliferation, and therefore support a potential role for cannabinoids in the treatment of psoriasis.[8]

Interactions

FABP5 has been shown to interact with S100A7.[

ABOUT CD47/SIRPa axis

CD47/SIRPa axis is established as a critical regulator of myeloid cell activation and serves as an immune checkpoint for macrophage mediated phagocytosis. Because of its frequent upregulation in several cancers, CD47 contributes to immune evasion and cancer progression. CD47 regulates phagocytosis primarily through interactions with SIRPla expressed on macrophages. Blockade of SIRPla/CD47 has been shown to dramatically enhance tumor cell phagocytosis and dendritic cells maturation for better antigen presentation leading to substantially improved antitumor responses in preclinical models of cancer (M. P. Chao et al. Curr Opin Immunol. 2012 (2): 225-232). Disruption of CD47-SIRPa interaction is now being evaluated as a therapeutic strategy for cancer with the use of monoclonal antibodies targeting CD47 or SIRPa and engineered receptor decoys.

CD47 is expressed on virtually all non-malignant cells, and blocking the CD47 or the loss of CD47 expression or changes in membrane distribution can serve as markers of aged or damaged cells, particularly on red blood cells (RBC). Alternatively, blocking SIRPa also allows engulfment of targets that are not normally phagocytosed, for those cells where pre-phagocytic signals are also present. CD47 is a broadly expressed transmembrane glycoprotein with a single Ig-like domain and five membrane- spanning regions, which functions as a cellular ligand for SIRPa with binding mediated through the NH2-terminal V-like domain of SIRPa. SIRPa is expressed primarily on myeloid cells, including macrophages, granulocytes, myeloid dendritic cells (DCs), mast cells, and their precursors, including hematopoietic stem cells.

CD47 is also constitutively upregulated on a number of cancers such as Non-Hodgkin Lymphoma (NHL), Acute myeloid leukemia (AML), breast, colon, glioblastoma, glioma, ovarian, bladder and prostate cancers, etc. Overexpression of CD47 by tumor cells, which efficiently helps them to escape immune surveillance and killing by innate immune cells. However, in most of the tumor types, blockade of the CD47-SIRPa interaction as a single agent may not be capable of inducing significant phagocytosis and antitumor immunity, necessitating the need to combine with other therapeutic agents. The concomitant engagement of activating receptors such as Fc-receptors (FcRs) or other prophagocytic receptors (collectively known as “eat-me” signals) may be necessary for exploiting the maximum potential of the CD-47-SIPRa pathway blockade.

The role of engagement of prophagocytic receptors is proved by inefficiency to trigger phagocytosis either by anti-CD47 F(ab) fragments, single chain variable fragments of CD-47 or non-Fc portion- containing SIRPa proteins in blocking of the CD47-SIRPa interaction. When activating prophagocytic receptors are engaged, as evident in the case of using Fc portion-containing blocking anti-CD47 antibodies, CD47- SIRPa blockade is able to trigger more efficient phagocytosis. Combining CD47-SIRPa blocking agents with therapeutic antibodies (Fc-containing) targeting tumor antigens stimulate activating Fc receptors (FcRs) leading to efficient phagocytosis. The Fc portion of therapeutic antibody targeting tumor antigen also induces antibody-dependent cellular cytotoxicity (ADCC), which also adds to the therapeutic efficacy. Hence antibodies selected from the group consisting of rituximab, herceptin, trastuzumab, alemtuzumab, bevacizumab, cetuximab and panitumumab, daratumumab due to its tumor targeting nature and ADCC, can trigger more efficient phagocytosis.

Earlier approaches to disrupt CD47- SIRPa interaction utilized monoclonal antibodies targeting CD47 or SIRPa and engineered receptor decoys fused to Fc fragment. However, a concern with this approach is that CD47 is highly expressed on both hematopoietic and non-hematopoietic normal cells. Hence along with tumor cells CD47-SIRPa blocking agents containing Fc-portion may also target many normal cells potentially leading to their elimination by macrophages. The interaction of blocking antibodies with normal cells is considered as a major safety issue resulting in anemia, thrombocytopenia, and leukopenia. These agents may also affect solid tissues rich in macrophages such as liver, lung, and brain. Hence it may be ideal to block the CD47- SIRPa interaction by agents devoid of Fc portion, such as small

molecules, peptides, Fab fragments etc. while activating prophagocytic receptors in tumor cells by appropriate combinations to induce efficient phagocytosis of tumor cells.

Apart from Fc Receptors, a number of other prophagocytic receptors are also reported to promote engulfment of tumor cells in response to CD47-SIRPa blockade by triggering the phagocytosis. These include receptors for SLAMF7, Mac-l, calreticulin and possibly yet to identified receptors. B cell tumor lines such as Raji and other diffuse large B cell lymphoma express SLAMF7 and are implicated in triggering prophagocytic signals during CD47-SIRPa blockade.

Therapeutic agents known to activate prophagocytic receptors are also therefore ideal partners for use in combination with CD47-SIRPa blocking agents to achieve efficient phagocytosis. These agents include proteasome inhibitors (bortezomib, ixazomib and carfilzomib), Anthracyclines (Doxorubicin, Epirubicin, Daunorubicin, Idarubicin, Mitoxantrone) Oxaliplatin, Cyclophosphamide, Bleomycin, Vorinostat, Paclitaxel, 5-Fluorouracil, Cytarabine, BRAF inhibitory drugs (Dabrafenib, Vemurafenib), PI3K inhibitor, Docetaxel, Mitomycin C, Sorafenib, Tamoxifen and oncolytic viruses.

Apart from the specific agents known to have effect on‘eat me’ signals other agents including Abiraterone acetate, Afatinib, Aldesleukin, Aldesleukin, Alemtuzumab, Anastrozole, Axitinib, Belinostat, Bendamustine, Bicalutamide, Blinatumomab, Bosutinib, Brentuximab, Busulfan, Cabazitaxel, Capecitabine, Carboplatin, Carfilzomib, Carmustine, Ceritinib, Clofarabine, Crizotinib, Dacarbazine, Dactinomycin, Dasatinib, Degarelix, Denileukin, Denosumab, Enzalutamide, Eribulin, Erlotinib, Everolimus, Exemestane, Exemestane, Fludarabine, Fulvestrant, Gefitinib, Goserelin, Ibritumomab, Imatinib, Ipilimumab, Irinotecan, Ixabepilone, Lapatinib, Lenalidomide, Letrozole, Leucovorin, Leuprolide, Lomustine, Mechlorethamine, Megestrol, Nelarabine, Nilotinib, Nivolumab, Olaparib, Omacetaxine, Palbociclib, Pamidronate, Panitumumab, Panobinostat, Pazopanib, Pegaspargase, Pembrolizumab, Pemetrexed Disodium, Pertuzumab, Plerixafor, Pomalidomide, Ponatinib, Pralatrexate, Procarbazine, Radium 223, Ramucirumab, Regorafenib, rIFNa-2b, Romidepsin, Sunitinib, Temozolomide, Temsirolimus, Thiotepa, Tositumomab, Trametinib, Vinorelbine, Methotrexate, Ibrutinib, Aflibercept, Toremifene, Vinblastine, Vincristine, Idelalisib, Mercaptopurine and Thalidomide could potentially have effect on‘eat me’ signal pathway on combining with CD-47-SIRPa blocking agents.

In addition to the therapeutic agents mentioned above, other treatment modalities that are in use in cancer therapy also activate prophagocytic receptors, and thus can be combined with CD47-SIRPa blocking agents to achieve efficient phagocytosis. These include Hypericin-based photodynamic therapy (Hyp-PDT), radiotherapy, High-hydrostatic pressure, Photofrin-based PDT and Rose Bengal acetate -based PDT.

However, there is an unmet need for combining small molecule CD-47-SIRPa pathway inhibitors with agents capable of stimulating activating receptors such as Fc-receptors (FcRs) or other prophagocytic receptors, or combining with other treatment modalities that are in use in cancer therapy to activate prophagocytic receptors for exploiting the maximum potential of the CD-47- SIRPa pathway blockade.

CLIP

Exelixis In-Licenses Second Anti-Cancer Compound from Aurigene Following FDA Acceptance of Investigational New Drug Application for Phase 1 Clinical Trial in Non-Hodgkin’s Lymphoma

– Robust preclinical data support Exelixis’ clinical development of XL114, with phase 1 trial in Non-Hodgkin’s lymphoma expected to begin in the coming months –

– Exelixis will make an option exercise payment of $10 million to Aurigene –

https://www.businesswire.com/news/home/20211014005549/en/Exelixis-In-Licenses-Second-Anti-Cancer-Compound-from-Aurigene-Following-FDA-Acceptance-of-Investigational-New-Drug-Application-for-Phase-1-Clinical-Trial-in-Non-Hodgkin%E2%80%99s-LymphomaOctober 14, 2021 08:00 AM Eastern Daylight Time

ALAMEDA, Calif.–(BUSINESS WIRE)–Exelixis, Inc. (Nasdaq: EXEL) and Aurigene Discovery Technologies Limited (Aurigene) today announced that Exelixis has exercised its exclusive option under the companies’ July 2019 agreement to in-license XL114 (formerly AUR104), a novel anti-cancer compound that inhibits the CARD11-BCL10-MALT1 (CBM) signaling pathway, which promotes lymphocyte survival and proliferation. Exelixis has now assumed responsibility for the future clinical development, commercialization and global manufacturing of XL114. Following the U.S. Food and Drug Administration’s (FDA) recent acceptance of its Investigational New Drug (IND) application, Exelixis will soon initiate a phase 1 clinical trial evaluating XL114 monotherapy in patients with Non-Hodgkin’s lymphoma (NHL). At the American Association of Cancer Research Annual Meeting in April of this year, Aurigene presented preclinical data (Abstract 1266) demonstrating that XL114 exhibited potent anti-proliferative activity in a large panel of cancer cell lines ranging from hematological cancers to solid tumors with excellent selectivity over normal cells. In addition, oral dosing of XL114 resulted in significant dose-dependent tumor growth inhibition in diffuse large B-cell lymphoma (DLBCL) and colon carcinoma models.

“We are pleased that our agreement with Aurigene has generated a second promising compound that warrants advancement into clinical development and believe the collaboration will continue to play an important role in expanding our pipeline”

XL114 is the second molecule that Exelixis in-licensed from Aurigene under the companies’ July 2019 collaboration, option and license agreement. Exelixis previously exercised its option to in-license XL102, a potent, selective and orally bioavailable inhibitor of cyclin-dependent kinase 7 (CDK7), from Aurigene in December 2020 and initiated a phase 1 trial of XL102 as a single agent and in combination with other anti-cancer agents in patients with advanced or metastatic solid tumors in January 2021.

“We are pleased that our agreement with Aurigene has generated a second promising compound that warrants advancement into clinical development and believe the collaboration will continue to play an important role in expanding our pipeline,” said Peter Lamb, Ph.D., Executive Vice President, Scientific Strategy and Chief Scientific Officer, Exelixis. “XL114 has shown potent anti-proliferative activity in lymphoma cell lines that have aberrant activation of the CBM signaling pathway and may have a differentiated profile and potential as a best-in-class molecule that could improve outcomes for patients with Non-Hodgkin’s lymphoma and other hematologic cancers.”

XL114 was identified to have anti-proliferative activity in cell lines with constitutive activation of CBM signaling, including activated B-cell-like DLBCL (ABC-DLBCL), mantle cell lymphoma and follicular lymphoma cell lines. Further characterization of XL114 in cell-based assays demonstrated a functional role in B-cell (BCR) signaling pathways. Additionally, XL114 showed dose-dependent tumor growth inhibition in an ABC-DLBCL mouse xenograft tumor model. In preclinical development, XL114 also demonstrated a high degree of selectivity against a broad safety pharmacology panel of enzymes and receptors. While the precise molecular mechanism underlying XL114’s function in repressing BCR signaling and MALT1 activation has yet to be characterized, the fatty acid-binding protein 5 (FABP5) has been identified as a prominent XL114-binding target.

“XL114 is the second molecule that Exelixis has opted to in-license under our July 2019 agreement, underscoring the significant potential of our approach to the discovery and preclinical development of innovative cancer therapies that target novel mechanisms of action,” said Murali Ramachandra, Ph.D., Chief Executive Officer, Aurigene. “Exelixis has a track record of success in the clinical development and commercialization of anti-cancer therapies that provide patients with important new treatment options, and we are pleased that the continued advancement of XL114 will be supported by the company’s extensive clinical, regulatory and commercialization infrastructure.”

Under the terms of the July 2019 agreement, Exelixis made an upfront payment of $10 million for exclusive options to obtain an exclusive license from Aurigene to three preexisting programs, including the compounds now known as XL102 and XL114. In addition, Exelixis and Aurigene initiated three Aurigene-led drug discovery programs on mutually agreed upon targets, in exchange for an additional upfront payment of $2.5 million per program. The collaboration was expanded in 2021 to include three additional early discovery programs. Exelixis is also contributing research funding to Aurigene to facilitate discovery and preclinical development work on all nine programs. Exelixis may exercise its option for a program at any time up until the first IND for the program becomes effective. Having exercised options on two programs thus far (XL102 and XL114), if and when Exelixis exercises a future option, it will make an option exercise payment to Aurigene and assume responsibility for that program’s future clinical development and commercialization including global manufacturing. To exercise its option for XL114, Exelixis will make an option exercise payment to Aurigene of $10 million. Once Exelixis exercises its option for a program, Aurigene will be eligible for clinical development, regulatory and sales milestones, as well as royalties on future potential sales of the compound. Under the terms of the agreement, Aurigene retains limited development and commercial rights for India and Russia.

About Aurigene

Aurigene Discovery Technologies Limited is a development stage biotech company engaged in discovery and clinical development of novel and best-in-class therapies to treat cancer and inflammatory diseases and a wholly owned subsidiary of Dr. Reddy’s Laboratories Ltd. (BSE: 500124, NSE: DRREDDY, NYSE: RDY, NSEIFSC: DRREDDY). Aurigene is focused on precision-oncology, oral immune checkpoint inhibitors, and the Th-17 pathway. Aurigene’s programs currently in clinical development include an oral ROR-gamma inhibitor AUR101 for moderate to severe psoriasis in phase 2 under a U.S. FDA IND and a PD-L1/VISTA antagonist CA-170 for non-squamous non-small cell lung cancer in phase 2b/3 in India. Additionally, Aurigene has multiple compounds at different stages of pre-clinical development. Aurigene has also partnered with several large and mid-pharma companies in the U.S. and Europe and has multiple programs in clinical development. For more information, please visit Aurigene’s website at www.aurigene.com.

About Exelixis

Founded in 1994, Exelixis, Inc. (Nasdaq: EXEL) is a commercially successful, oncology-focused biotechnology company that strives to accelerate the discovery, development and commercialization of new medicines for difficult-to-treat cancers. Following early work in model system genetics, we established a broad drug discovery and development platform that has served as the foundation for our continued efforts to bring new cancer therapies to patients in need. Our discovery efforts have resulted in four commercially available products, CABOMETYX® (cabozantinib), COMETRIQ® (cabozantinib), COTELLIC® (cobimetinib) and MINNEBRO® (esaxerenone), and we have entered into partnerships with leading pharmaceutical companies to bring these important medicines to patients worldwide. Supported by revenues from our marketed products and collaborations, we are committed to prudently reinvesting in our business to maximize the potential of our pipeline. We are supplementing our existing therapeutic assets with targeted business development activities and internal drug discovery – all to deliver the next generation of Exelixis medicines and help patients recover stronger and live longer. Exelixis is a member of the Standard & Poor’s (S&P) MidCap 400 index, which measures the performance of profitable mid-sized companies. In November 2020, the company was named to Fortune’s 100 Fastest-Growing Companies list for the first time, ranking 17th overall and the third-highest biopharmaceutical company. For more information about Exelixis, please visit www.exelixis.com, follow @ExelixisInc on Twitter or like Exelixis, Inc. on Facebook.

Dinesh Chikkanna

Dinesh Chikkanna

Director, Medicinal Chemistry Aurigene Discovery Technologies

Murali Ramachandra

Murali Ramachandra

CEO at Aurigene Discovery Technologies

str1

CLIP

https://cancerres.aacrjournals.org/content/81/13_Supplement/1266

Abstract 1266: Discovery and preclinical evaluation of a novel covalent inhibitor of FABP5 for cancer therapyDinesh Chikkanna, Leena Khare Satyam, Sunil Kumar Pnaigrahi, Vinayak Khairnar, Manoj Pothuganti, Lakshmi Narayan Kaza, Narasimha Raju Kalidindi, Vijaya Shankar Nataraj, Aditya Kiran Gatta, Narasimha Rao Krishnamurthy, Sandeep Patil, DS Samiulla, Kiran Aithal, Vijay Kamal Ahuja, Nirbhay Kumar Tiwari, KB Charamannna, Pravin Pise, Thomas Anthony, Kavitha Nellore, Sanjeev Giri, Shekar Chelur, Susanta Samajdar and Murali Ramachandra 
DOI: 10.1158/1538-7445.AM2021-1266 Published July 2021 
Proceedings: AACR Annual Meeting 2021; April 10-15, 2021 and May 17-21, 2021; Philadelphia, PA

Abstract

Dysregulated fatty acid metabolism is thought to be a hallmark of cancer, wherein fatty acids function both as an energy source and as signals for enzymatic and transcriptional networks contributing to malignancy. Fatty acid-binding protein 5 (FABP5) is an intracellular protein that facilitates transport of fatty acids and plays a role in regulating the expression of genes associated with cancer progression such as cell growth, survival, and metastasis. Overexpression of FABP5 has been reported to contribute to an aggressive phenotype and a poor survival correlation in several cancers. Therefore, inhibition of FABP5 is considered as a therapeutic approach for cancers. Phenotypic screening of a library of covalent compounds for selective sensitivity of cancer cells followed by medicinal chemistry optimization resulted in the identification of AUR104 with desirable properties. Chemoproteomic-based target deconvolution revealed FABP5 as the cellular target of AUR104. Covalent adduct formation with Cys43 of FABP5 by AUR104 was confirmed by mass spectrometry. Target occupancy studies using a biotin-tagged AUR104 demonstrated potent covalent binding to FABP5 in both cell-free and cellular conditions. Ligand displacement assay with a fluorescent fatty acid probe confirmed the competitive binding mode of AUR104 with fatty acids. Binding at the fatty acid site and covalent bond formation with Cys43 were also demonstrated by crystallography. Furthermore, AUR104 showed a high degree of selectivity against a broad safety pharmacology panel of enzymes and receptors. AUR104 exhibited potent anti-proliferative activity in a large panel of cell lines derived from both hematological and solid cancers with a high degree of selectivity over normal cells. Anti-proliferative activity in lymphoma cell lines correlated with inhibition of MALT1 pathway activity, cleavage of RelB/Bcl10 and secretion of cytokines, IL-10 and IL-6. AUR104 displayed desirable drug-like properties and dose-dependent oral exposure in pharmacokinetic studies. Oral dosing with AUR104 resulted in dose-dependent anti-tumor activity in DLBCL (OCI-LY10) and NSCLC (NCI-H1975) xenograft models. In a repeated dose MTD studies in rodents and non-rodents, AUR104 showed good tolerability with an exposure multiple of >500 over cellular EC50 for up to 8 hours. In summary, we have identified a novel covalent FABP5 inhibitor with optimized properties that showed anti-tumor activity in in vitro and in vivo models with acceptable safety profile. The data presented here strongly support clinical development of AUR104.

Citation Format: Dinesh Chikkanna, Leena Khare Satyam, Sunil Kumar Pnaigrahi, Vinayak Khairnar, Manoj Pothuganti, Lakshmi Narayan Kaza, Narasimha Raju Kalidindi, Vijaya Shankar Nataraj, Aditya Kiran Gatta, Narasimha Rao Krishnamurthy, Sandeep Patil, DS Samiulla, Kiran Aithal, Vijay Kamal Ahuja, Nirbhay Kumar Tiwari, KB Charamannna, Pravin Pise, Thomas Anthony, Kavitha Nellore, Sanjeev Giri, Shekar Chelur, Susanta Samajdar, Murali Ramachandra. Discovery and preclinical evaluation of a novel covalent inhibitor of FABP5 for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1266.

Patent

US20200147054 – COMBINATION OF SMALL MOLECULE CD-47 INHIBITORS WITH OTHER ANTI-CANCER AGENTS

Muralidhara Ramachandra
Pottayil Govindan Nair Sasikumar
Girish Chandrappa Daginakatte
Kiran Aithal Balkudru

PATENT

WO 2020095256

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020095256

Example- 1: The synthetic procedures for the preparation of compounds described in the present invention were described in co-pending Indian provisional patent application 201841001438 dated 12* Jan 2018, which is converted as PCT application

PCT/IB2019/050219, the contents of which are hereby incorporated by reference in their entirety.

str1

PATENT

WO 2018178947https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018178947&tab=PCTDESCRIPTION

PATENT

WO 2019138367

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019138367

PATENT

WO 2019073399

https://patents.google.com/patent/WO2019073399A1/en

Priority to IN201741036169

Example 4 of WO 2015/033299

Figure imgf000002_0001
Figure imgf000003_0002

PATENT

https://patents.google.com/patent/BR112020014202A2/en

wdt-16

join me on Linkedin

Anthony Melvin Crasto Ph.D – India | LinkedIn

join me on Researchgate

RESEARCHGATE

This image has an empty alt attribute; its file name is research.jpg

join me on Facebook

Anthony Melvin Crasto Dr. | Facebook

join me on twitter

Anthony Melvin Crasto Dr. | twitter

+919321316780 call whatsaapp

EMAIL. amcrasto@amcrasto

/////////////////////////////////////////////////////////////////////////////////////////////////////

PATENT

The present invention relates to substituted alkynylene compounds represented by compound of formula (I) pharmaceutically acceptable salts and stereoisomers thereof. The present invention further provides the methods of preparation of compound of formula (I) and therapeutic uses thereof as anti-cancer agents.

Patent

Example 1

(((S)-4-amino-1-(3-((S)-1,5-diaminopentyl)-1,2,4-oxadiazol-5-yl)-4-oxobutyl)carbamoyl)-L-proline (Compound 1)


 (MOL) (CDX)

Synthesis of Compound 1 b


 (MOL) (CDX)
      Ethylchloroformate (2.47 mL, 25.9 mmol) and NMM (2.9 mL, 25.9 mmol) were added to a solution of compound 1a (6.0 g, 17.3 mmol) in THF (60 mL) and stirred at −20° C. for 20 min. After 20 minutes 25% of aq.ammonia (24 mL) was added to the active mixed anhydride resulting from the reaction and the reaction mass was stirred at 0-5° C. for 30 min. The completeness of the reaction was confirmed by TLC analysis. The volatiles were evaporated under reduced pressure and partitioned between water and ethyl acetate. The organic layer was washed with NaHCO solution followed by citric acid solution and brine solution. The separated organic layer was dried over Na 2SO 4, filtered and evaporated under reduced pressure to yield 5.6 g of compound 1 b. LCMS: 346.4 [M+H] +.

Synthesis of Compound 1C


 (MOL) (CDX)
      Trifluroacetic anhydride (6.85 mL, 48.6 mmol) was added to a solution of compound 1b (5.6 g, 16.2 mmol), pyridine (7.84 mL, 97.2 mmol) in DCM (60 mL) at 0° C. and stirred at room temperature for an hour. The completion of the reaction was confirmed by TLC analysis. The volatiles were evaporated under reduced pressure and partitioned between water and CH 2Cl 2. The organic layer was washed with NaHCO solution followed by citric acid and brine solution. The separated organic layer was dried over Na 2SO 4, filtered and evaporated under reduced pressure to yield 5.42 g of compound 1c, which was used for next step directly.

Synthesis of Compound 1d


 (MOL) (CDX)
      Hydroxylamine hydrochloride (3.43 g, 49.5 mmol), water (10 mL) and K 2CO (4.54 g, 32.9 mmol) were added to a solution of compound 1c (5.4 g, 16.5 mmol) in EtOH (60 mL) and stirred at room temperature for overnight. The completion of the reaction was confirmed by TLC analysis. After the completion of reaction, the compound from the water was extracted by using the CH 2Cl followed washing the organic layer with water, brine and concentrated under reduced pressure to yield 5.8 g of compound 1d. LCMS: 361.3 [M+H] +.

Synthesis of Compound 1f


 (MOL) (CDX)
      HOBt (3.24 g, 24.0 mmol) and DIC (3.36 mL, 24.0 mmol) were added to a solution of Fmoc-Gln(Trt)-OH (compound 1e) (9.83 g, 16.1 mmol) in DMF (100 mL) at 0° C. and stirred for 15 min. Compound 1d (5.8 g, 16.1 mmol) was added to the reaction mass at the same temperature and the resulting mixture was stirred for an hour at the same temperature, followed by stirring at room temperature for an additional 2 h. The completion of the reaction was confirmed by TLC analysis. The reaction mixture was quenched with ice water; precipitated white solid was filtered; washed with water (150 mL) and dried under high under reduced pressure to yield 8.62 g of compound 1f. LCMS: 953.7 [M+H] +.

Synthesis of Compound 1g


 (MOL) (CDX)
      Acetic acid (5 mL) was added to a solution of compound 1f (5.0 g, 5.0 mmol) in acetonitrile (50 ml) at room temperature and the reaction mass was refluxed at 85° C. for 12 h. The completion of the reaction was confirmed by TLC analysis. The volatiles were evaporated under reduced pressure to obtain crude semi solid which was diluted with water and ethyl acetate. The organic layer was washed with NaHCO solution followed by citric acid and brine solution. The organic layer was dried over Na 2SO 4; filtered and evaporated under reduced pressure to obtain crude solid. Compound was purified using column chromatography to yield 4.3 g of title compound. LCMS: 935.6 [M+H] +.

Synthesis of Compound 1h


 (MOL) (CDX)
      Compound 1g (4.3 g, 4.5 mmol) was added to a solution of 20% piperidine in DMF (20 mL) at 0° C. and the reaction mass was stirred at same temperature for an hour. The completion of the reaction was confirmed by TLC analysis. After completion, the reaction mixture was quenched with ice-cold water and the resulting white precipitate was filtered and dried under vacuum. The crude product obtained was diluted with hexane, stirred and filtered to yield 3.0 g of compound 1h. LCMS: 713.4 [M+H] +.

Synthesis of Compound 1i


 (MOL) (CDX)
      Pyridine (0.33 mL, 4.2 mmol) was added to a solution of compound 1h (1.5 g, 2.1 mmol) in CH 2Cl (15 mL) and the resulting solution was stirred at room temperature for 10 min. 4-nitrophenyl chloroformate (0.84 g, 4.2 mmol) in CH 2Cl (15 mL) was added to the above mixture and the resultant mixture was stirred at room temperature for an hour. After completion of reaction (confirmed by TLC), it was diluted with CH 2Cl (50 mL) and washed with water (100 mL×2), 1N HCl (100 mL×2), water followed by brine solution (100 mL×2). The organic layer was dried over Na 2SO 4; filtered and evaporated under reduced pressure to yield 0.72 g compound 1i, which was taken to the next step without any further purification. LCMS: 878.9 [M-100].

Synthesis of compound 1j


 (MOL) (CDX)
      TEA (0.34 mL, 2.46 mm) was added to a solution of H-Pro-O tBu.HCl (0.21 g, 1.23 mmol) and compound 1i (0.72 g, 0.82 mmol) in THF (10 mL) at room temperature and stirred for 12 h. The volatiles were evaporated and portioned between ethyl acetate and water. The reaction mixture was diluted with ice cold water and extracted with EtOAc. The Organic layer was separated and dried over Na 2SO and concentrated under reduced pressure. The crude compound obtained was purified by column chromatography and compound elutes in 50% of ethyl acetate in hexane. Yield: 0.5 g of compound 1j. LCMS: 910.6 [M+H] +.

Synthesis of Compound 1


 (MOL) (CDX)
      Compound 1j (0.5 g, 0.55 mmol) was added to a cocktail mixture (10 m L) of TFA:TIPS:H 2O (95:2.5:2.5) and was stirred at room temperature for 3 h. The resulting reaction mixture was evaporated under reduced pressure, diluted with diethyl ether and filtered to yield 0.2 g of crude compound 1. The crude solid material was purified by preparative HPLC method described under experimental conditions. LCMS: 412.2 [M+H] +. HPLC t (min): 9.6.

Example 2

(S)-4-(3-((S)-1-amino-4-guanidinobutyl)-1,2,4-oxadiazol-5-yl)-4-(3-((S)-1-carboxy-2-phenylethyl) ureido)butanoic acid (Compound 7)


 (MOL) (CDX)

Synthesis of Compound 2b


 (MOL) (CDX)
      Ethylchloroformate (1.75 mL, 18.23 mmol) and NMM (2.0 mL, 18.23 mmol) were added into a solution of compound 2a (8.0 g, 15.18 mmol) in THF (45 mL) and the resulting mixture was stirred at −20° C. for 20 min. After 20 minutes 25% of aqueous ammonia (25 mL) was added to the active mixed anhydride generated and stirred at 0-5° C. for 30 min. The completeness of the reaction was confirmed by TLC analysis. The volatiles were evaporated under reduced pressure and partitioned between water and ethyl acetate. The organic layer was washed with NaHCO solution followed by citric acid solution and brine solution. The separated organic layer was dried over Na 2SO 4, filtered and evaporated under reduced pressure to yield 7.1 g of compound 2b. LCMS: 526.3 [M+H] +.

Synthesis of Compound 2c


 (MOL) (CDX)
      Trifluroacetic anhydride (TFAA) (2.83 mL, 20.26 mmol) was added to a solution of compound 2b (7.1 g, 13.51 mmol) in pyridine (7.08 g, 87.80 mmol) and the resulting mixture was stirred at room temperature for 2 h. The completion of the reaction was confirmed by TLC analysis. The volatiles were evaporated under reduced pressure and partitioned between water and ethyl acetate. The organic layer was washed with citric acid and brine solution. The separated organic layer was dried over Na 2SO 4, filtered and evaporated under reduced pressure. The crude solid was purified via column chromatography (60-120 silicagel) to yield 5.8 g of compound 2c. LCMS: 508.3 [M+H] +.

Synthesis of Compound 2d


 (MOL) (CDX)
      Hydroxylamine hydrochloride (1.56 g, 22.50 mmol), water (30 mL) and potassium carbonate (3.11 g, 11.25 mmol) were added to a solution of compound 2c (5.8 g, 11.25 mmol) in EtOH (60 mL) and stirred at 90° C. for 3 h. The completion of the reaction was confirmed by TLC analysis. The volatiles were evaporated under reduced pressure and partitioned between water and ethyl acetate. The organic layer was washed with brine solution, dried over Na 2SO then filtered and evaporated under reduced pressure, the solid obtained was washed with 20% ethyl acetate to yield 6.1 g of compound 2d. LCMS: 541.3 [M+H] +.

Synthesis of Compound 2f


 (MOL) (CDX)
      HOBt (2.28 g, 16.9 mmol) and DIC (2.62 mL, 16.9 mmol) were added to a solution of Fmoc-Glu(O tBu)-OH (compound 2e) (4.0 g, 9.02 mmol) in DMF (60 mL) at 0° C. and the resulting mixture was stirred for 15 min. Then compound 2d (6.1 g, 11.28 mmol) was added to the above mixture at the same temperature and the reaction mixture was continued stirring for an hour and then at room temperature for 2 h. The completion of the reaction was confirmed by TLC analysis. The reaction mixture was quenched with ice cold water, the precipitated white solid was filtered, washed with water (150 mL) and dried under high under reduced pressure. The solid was taken into 10% MeOH in DCM and washed the organic layer with 10% NaHCO 3, water and brine solution. The organic layer was dried over Na 2SO and concentrated under reduced pressure to yield 8.0 g of compound 2f. LCMS: 948.7 [M+H] +.

Synthesis of Compound 2g


 (MOL) (CDX)
      Acetic acid (7 mL) was added to a solution of compound 2f (7.0 g, 7.38 mmol) in THF (70 ml) at room temperature and the resulting mixture was refluxed at 70° C. for 12 h. The completion of the reaction was confirmed by TLC analysis. The volatiles were evaporated under reduced pressure to obtain crude semi solid which was diluted with water and ethyl acetate. The organic layer was washed with NaHCO solution followed by brine solution. The organic layer was dried over Na 2SO 4, filtered and evaporated under reduced pressure to get crude solid. The compound was purified by column chromatography (60-120 silicagel) to yield 5.4 g of compound 2g. LCMS: 930.5 [M+H] +.

Synthesis of Compound 2h


 (MOL) (CDX)
      Compound 2g (5.4 g, 5.80 mmol) was added to a solution of 50% piperidine in DMF (20 mL) at 0° C. and stirred at same temperature for 2 h. The completion of the reaction was confirmed by TLC analysis. The reaction mass was quenched with water (100 mL), the resulted precipitate was filtered. The solid obtained was dissolved in ethyl acetate and washed the organic layer with 10% NaHCO 3, water and brine. The organic layer was dried over Na 2SO and concentrated under reduced pressure. The crude product obtained was diluted with hexane and the resulted precipitate was filtered followed by washing with hexane to obtain 3.0 g of compound 2h. LCMS 708.6 [M+H] +.

Synthesis of Compound 2i


 (MOL) (CDX)
      Pyridine (0.75 mL, 9.3 mmol) was added to a solution of H-Phe-O tBu.HCl (2.0 g, 7.75 mmol) in CH 2Cl (20 mL) was added pyridine and the resulting solution was stirred at room temperature for 10 min. To this reaction mixture a solution of 4-nitrophenyl chloroformate (1.87 g, 9.30 mmol) in CH 2Cl (20 mL) was added and the resultant mixture was stirred at room temperature for 3 h. After completion of reaction (confirmed by TLC) it was diluted with CH 2Cl (50 mL) and washed with water (100 mL×2), 10% citric acid (100 mL×2), water (100 mL), followed by brine solution (100 mL). The organic layer was dried over Na 2SO 4, filtered and evaporated under reduced pressure to yield 1.7 g compound 2i, which was taken to the next step without any further purification.

Synthesis of Compound 2j


 (MOL) (CDX)
      TEA (0.29 mL, 2.1 mmol) was added to a solution of compound 2h (1.0 g, 1.41 mmol) and compound 2i (0.54 g, 1.41 mmol) in THF (10 mL) at room temperature and stirred for 3 h. The volatiles were evaporated and portioned between EtOAc and water. The reaction mixture was diluted with ice cold water and extracted with EtOAc followed by washing with 10% K 2CO (100 mL×4), water and brine solution. Organic layer separated and dried over Na 2SO and concentrated under reduced pressure. The crude product obtained was diluted with hexane and the resulted precipitate was filtered followed by washing with hexane yielded 0.98 g of compound 2j. LCMS: 955.6 [M+H] +.

Synthesis of Compound 7


 (MOL) (CDX)
      Compound 2j (0.5 g, 5.2 mmol) was added to cocktail mixture (5 m L) of trifluoroacetic: TIPS: water (95:2.5:2.5). The cleavage solution was stirred at room temperature for 3 h. The resulting reaction mixture was evaporated under reduced pressure, diluted with diethyl ether and filtered to yield 0.34 g of crude compound 2. The crude solid material was purified by preparative HPLC method as described under experimental conditions. LCMS: 491.1 [M+H] +. HPLC t R: (min): 11.1

PATENT

WO 2015/033299

https://patents.google.com/patent/WO2015033299A1/en?oq=WO+2015%2f033299

Pottayil Govindan Nair SasikumarMuralidhara RamachandraSeetharamaiah Setty Sudarshan Naremaddepalli

Figure imgf000024_0001

Example 1: Synthesis of Compound 1

Figure imgf000019_0001

Step la:

Figure imgf000019_0002

Ethylchloroformate (1.5 g, 13.78 mniol) and N-Methylmorpholine ( 1.4 g, 13.78 mmol) were added to a solution of compound la (3 g, 11.48 mmol) in THE (30 mL) arid stirred at -20 °C. After 20 min. Liquid ammonia (0.77 g, 45.92 mmol) was added to the active mixed anhydride formed in- situ and stirred at 0-5 °C for 20 min. The completeness of the reaction was confirmed by TLC analysis. The reaction mixture was evaporated under reduced pressure and partitioned between water and ethyl acetate. Organic layer was washed with NaHCOs, citric acid, brine solution, dried over Na2S04 and evaporated under reduced pressure to get 2.9 g of compound lb (Yield: 96.3%). LCMS: 261.0 ( Vi+H ; .

Step lb:

Figure imgf000020_0001

1 b 1cTrifluroacetic anhydride (9.7 g, 46.0 mmol) was added to a solution of compound lb (8 g, 30.7 mmol) in pyridine (24.3 g, 307.0 mmol) and stirred at room temperature for 3 h. The completeness of the reaction was confirmed by TLC analysis. The reaction mixture was evaporated under reduced pressure and partitioned between water and ethyl acetate. Organic layer was washed with NaHCO?,, citric acid, brine solution, dried over Na2-S04 and evaporated under reduced pressure to afford 7 g of compound lc (Yield: 94.0%). LCMS: 187.2 (M-¾u )+.

Step lc:

Figure imgf000020_0002

1 c 1dHydroxylamine hydrochloride (3 g, 43.37 mmol) and potassium carbonate (6 g, 43.37 mmol) were added to a solution of compound lc (7 g, 28.91 mmol) in EtOH (70 m L) and stirred at 90 °C for 2 h. The completeness of the reaction was confirmed by TLC analysis. The reaction mixture was evaporated under reduced pressure and partitioned between water and ethyl acetate. Organic layer was washed with brine solution, dried over Na2S04 and evaporated under reduced pressure. The crude compound was purified by silica gel column chromatography (Eluent: 0-5% ethyl acetate in hexane) to get 4.2 g of compound Id (Yield: 52.8%). LCMS: 276.4 (M+H)+.Step Id:

Figure imgf000021_0001

Deoxo-Fluor® (1.83 g, 8.3 mmol) was added to a solution of Fmoc-Asn(Trt)-OH (4.5 g, 7.5 mmol) in CH2Q2 (50 mL) and stirred at 0 °C for 3 h. Then CH2CI2 was evaporated and triturated with hexane, decanted and evaporated under vacuum to get the corresponding acid fluoride. NMM (1.17 g, 1 1.6 mmol) and compound Id (1.6 g, 5.8 mmol) in THF were added to the acid fluoride and stirred at room temperature for 12 h. Then THF was evaporated and sodium acetate (0.72 g, 8.7 mmol) was added followed by EtOH (50 mL). The reaction mixture was stirred at 90 °C for 2 h. The completeness of the reaction was confirmed by TLC analysis. The reaction mixture was evaporated under reduced pressure and partitioned between water and ethyl acetate. Organic layer was washed with NaHCOa, citric acid, brine solution, dried over Na2S04 and evaporated under reduced pressure, which was further purified by silica gel column chromatography (Eluent: 0-5% ethyl acetate in hexane) to afford 2.8 g of compound le (Yield: 44.4%). LCMS: 836.4 (M+Hf .Step le:

Ph3

Figure imgf000021_0002

To compound le (2.3 g, 2.7 mmol) in CH2CI2 (10 mL) diethyiarnine (10 mL) was added and the reaction mixture was stirred at room temperature for 30 min. The resulting solution was concentrated in vacuum to get gummy residue. The crude compound was purified by neutral alumina column chromatography (Eluent: 0-50% ethyl acetate in hexane then 0-5% methanol in chloroform) to get 1.4 g of If (Yield: 90 %). LCMS: 636.5 (M+Na)+.

Figure imgf000022_0001

1f 1To a solution of compound If (0.45 g) in CH2CI2 (5 mL), trifluoroacetic acid (5 mL) and catalytic amount of triisopropylsilane were added and stirred for 3 h at room temperature to remove the acid sensitive protecting groups. The resulting solution was concentrated in vacuum to afford 0.29 g of crude compound 1 which was purified using prep-HPLC method described under experimental conditions. \H NMR (DMSQ-d6, 400 MHz): δ 2.58 (m, 2H), 3.53 (m, 3H), 3.91 (t, 1H), 4.36 (t, 1H), 6.91 (s, 1H), 7.45 (s, 1H); 1 C NMR (DMSO-de, 400 MHz): δ 20.85, 45.71 , 50.23, 65.55, 171.03, 171 .41, 181.66. LCMS: 216.2 (Μ+ΗΓ; HPLC: tR = 13.1 min.Example 2: Synthesis of Co

Figure imgf000022_0002

Step 2a:

Figure imgf000022_0003

1f2a

The urea linkage was carried out by the coupling compound If (2.7 g, 4.39 mmoi) in THF (30 mL) at room temperature with compound 2b (1.67 g, 4.39 mmoi). The coupling was initiated by the addition of TEA (0.9 g, 8.78 mmoi) in THF (10 m L) and the resultant mixture was stirred at room temperature. After completion of 20 h, THF was evaporated from the reaction mass, and partitioned between water and ethyl acetate. Organic layer was washed with water, brine, dried over Na2S04 and evaporated under reduced pressure to get compound 2a, which was further purified by silica gel column chromatography (Fluent: 0-50% ethyl acetate in hexane) to afford 3.46 g of compound 2a (Yield: 92.10%). LCMS 857.4 (M+H)+.

Figure imgf000023_0001

2aTo a solution of compound 2a (0.22 g, 0.25 mmol) in 0¾ί¾ (5 m L), trifluoroaeetic acid (5 mL) and catalytic amount of triisopropyisilane were added and stirred for 3h at room, temperature. The resulting solution was concentrated under reduced pressure to obtain 0.35 g of crude compound. The crude solid material was purified using preparative- HPLC method described under experimental conditions. LCMS: 347.1 (M+H)+; HPLC: tR = 12.9 min.

Synthesis of

Figure imgf000023_0002

2bTo the compound H-Ser(tBu)-OiBu (2 g, 9.2 mmol) in C I I■(.{■ (20 mL), triethylamine (1.39 g, 13.8 mmol) was added and the solution was stirred at room temperature for 5-10 min. To this mixture, solution of 4-Nitrophenyl chioro formate (2.22 g, 11.04 mmol) in CH2CI2 was added and the resultant mixture was stirred at room temperature for 30 min. The completion of the reaction was confirmed by TLC analysis. After completion of reaction, reaction mixture was diluted with CH2CI2 and washed with water and 5.0 M citric acid solution, dried over Na2SC>4 and evaporated under reduced pressure to get crude compound 2b, which was further purified by silica gel column chromatography (Eiuent: 0-20% ethyl acetate in hexane) to yield 2.1 g (58.9%) of 2b.Example 3: Synthesis of Compound 3

Figure imgf000023_0003

The compound was synthesised using similar procedure as depicted in Example 1 (compound 1) and D-amino acids are linked up in reverse order. Boc-D-Thr(‘Bu)-OH was used in place of Boc-Ser(‘Bu)-OH (compound la, Example 1) and Fmoc-D- Asn(trt)-OH in place of Fmoc-Asn(trt)-OH to yield 0.15 g crude material of the title compound 3. LCMS: 230.1 (M+H)+.Example 4: Synthesis of Co

Figure imgf000024_0001

The compound was synthesised using similar procedure as depicted in Example 2 for synthesising compound 2 using

Figure imgf000024_0002

instead of H-Ser(‘Bu)-0’Bu (in synthesis of compound 2b) to yield 0.35 g crude material of the title compound. The crude solid material was purified using preparative HPLC described under experimental conditions. LCMS: 361.2 (M+H)+, HPLC: tR = 12.19 min.Example 5: Synthesis of

Figure imgf000024_0003

The compound was synthesised using similar procedure as depicted in Example 4 (compound 4) using D-amino acids are linked up in reverse order. Boc-D-Thr(‘Bu)-OH was used in place of Boc-Ser(‘Bu)-OH, Fmoc-D-Asn(trt)-OH in place of Fmoc-Asn(trt)- OH and H-D-Ser(‘Bu)-0’Bu was used in place of H-Thr^Bu^O’Bu to yield 0.3 g crude material of the title compound. The cmde solid material was purified using preparative HPLC described under experimental conditions. LCMS: 361.3 (M+H)+. HPLC: tR = 13.58 min.Example 6: Synthesis of Compound 6

Figure imgf000024_0004

The compound was synthesised using similar procedure as depicted in Example 2 by using H-Thr(‘Bu)-OMe instead of H-Ser(‘Bu)-0’Bu (in synthesis of compound 2b) to yield 0.2 g crude material of the title compound. The crude solid material was purified using preparative HPLC described under experimental conditions. LCMS: 375.1 (M+H)+, HPLC: tR = 1.84 min.Example 7: Synthesis of Compound 7

Figure imgf000025_0001

Step 7a:

Figure imgf000025_0002

1f7aThe compound 7a was synthesised using similar procedure as for compound 2a (Example 2, step 2a) using H-Thr(‘Bu)-OMe instead of H-Ser(‘Bu)-OtBu to get crude material which was further purified by silica gel column chromatography (Eluent: 0-50% ethyl acetate in he ane) to get 2.0 g of compound 7a (Yield: 74 %). LCMS: 829.2 (M+H)+.Step 7b:

Figure imgf000025_0003

7a 7bTo a solution of compound 7a (0.35 g, 4.0 mmol) in THF (5 mL) was added lithium hydroxide (0.026 g, 0.63 mmol) at 0 °C and the mixture was stirred for 2 h at room temperature. The completion of the reaction was confirmed by TLC analysis. THF was evaporated from the reaction mass, and partitioned between water and ethyl acetate. Organic layer was washed with citric acid, brine solution, dried over Na2S04 and evaporated under reduced pressure to afford 7b, which was further purified by silica gel column chromatography (Eluent: 0-5% methanol in DCM) to get 0.3 g of product 7b (Yield: 86.7%). LCMS 815.2 (M+H)+.

Step 7c:

Figure imgf000026_0001

7b 7Compound 7b (0.295 g, 0.39 mmol) was anchored to Rink amide resin (0.7 g, 0.55 mmol/g) using HOBT (0.072 g, 0.54 mmol) and DIC (0.068 g, 0.54 mmol) method in DMF (10 mL). The resin was stirred for 12 h at room temperature. The resin was washed with DCM, DMF and DCM and dried. The target compound was cleaved from the rink amide resin using TFA (5 mL) and catalytic amount of TIPS. The resin was allowed to remain at room temperature for 2 h with occasional stirring. After 2 h, TFA and TIPS were evaporated under nitrogen atmosphere and the resulting residue was washed with diethyl ether to yield 0.1 g crude material of the title compound 7. The crude solid material was purified using preparative HPLC described under experimental conditions. LCMS: 360.0 (M+H)+, HPLC: tR = 13.88 min.Example 8: Synthesis of

Figure imgf000026_0002

The compound was synthesised using similar procedure as depicted in Example 2 (compound 2) using Fmoc-Glu(0’Bu)-OH instead of Fmoc-Asn(Trt)-OH to get 0.4 g crude material of the title compound. The crude solid material was purified using preparative HPLC described under experimental conditions. LCMS: 362.1 (M+H)+. HPLC: tR = 13.27 min.

PATENThttps://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019061324&tab=FULLTEXT

Patenthttps://patents.google.com/patent/WO2019067678A1/enPATENThttps://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019061324

PATENThttps://patents.google.com/patent/WO2018073754A1/en
PATENThttps://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019087087
PAPERSScientific Reports (2019), 9(1), 1-19. https://www.nature.com/articles/s41598-019-48826-6

figure1

Chemical structures of PD-L1 inhibitors developed by Aurigene (Aurigene-1) and Bristol-Meyers Squibb (BMSpep-57, BMS-103, and BMS-142). Chemical structures were generated using ChemDraw Professional 15. PATENT
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019087087

L-threonine’ mentioned in compound of formula (I) thereof can be represented by any one of the following formulae:

Publication NumberTitlePriority DateGrant Date
US-2020289477-A1Conjoint therapies for immunomodulation2017-11-06 
WO-2019073399-A1CRYSTALLINE FORMS OF 1,2,4-OXADIAZOLE SUBSTITUTED IN POSITION 32017-10-11 
AU-2018341583-A1Crystal forms of immunomodulators2017-09-29 
WO-2019061324-A1CRYSTALLINE FORMS OF IMMUNOMODULATORS2017-09-29 
WO-2019067678-A1CRYSTALLINE FORMS OF IMMUNOMODULATORS2017-09-29
Publication NumberTitlePriority DateGrant Date
US-2020247766-A1Crystal forms of immunomodulators2017-09-29 
US-2020061030-A1Dual inhibitors of vista and pd-1 pathways2016-10-20 
WO-2018073754-A1Dual inhibitors of vista and pd-1 pathways2016-10-20 
US-2020361880-A11,2,4-Oxadiazole and Thiadiazole Compounds as Immunomodulators2015-03-10 
EP-3041827-B11,2,4-oxadiazole derivatives as immunomodulators2013-09-062018-04-18
Publication NumberTitlePriority DateGrant Date
EP-3363790-B11,2,4-oxadiazole derivatives as immunomodulators2013-09-062020-02-19
US-10173989-B21,2,4-oxadiazole derivatives as immunomodulators2013-09-062019-01-08
US-10590093-B21,2,4-oxadiazole derivatives as immunomodulators2013-09-062020-03-17
US-2015073024-A11,2,4-Oxadiazole Derivatives as Immunomodulators2013-09-06 
US-2017101386-A11,2,4-Oxadiazole Derivatives as Immunomodulators2013-09-06
Publication NumberTitlePriority DateGrant Date
US-2018072689-A11,2,4-Oxadiazole Derivatives as Immunomodulators2013-09-06 
US-2019144402-A11,2,4-Oxadiazole Derivatives as Immunomodulators2013-09-06 
US-2020199086-A11,2,4-Oxadiazole Derivatives as Immunomodulators2013-09-06 
US-9771338-B21,2,4-oxadiazole derivatives as immunomodulators2013-09-062017-09-26
WO-2015033299-A11,2,4-oxadiazole derivatives as immunomodulators2013-09-06

////////////Investigational New Drug Application,  Phase 1,  Clinical Trial, Non-Hodgkin’s Lymphoma, XL 114, AUR 104, aurigene, Exelixis 

N[C@@H](CO)c1nc(on1)[C@@H](NC(=O)N[C@H](C(=O)O)C(C)O)CC(N)=O

https://patentscope.wipo.int/search/en/result.jsf?inchikey=HFOBENSCBRZVSP-WHFCDURNSA-N

NEW DRUG APPROVALS

ONE TIME

$10.00

Click here to purchase.

PATENT

The present invention relates to substituted alkynylene compounds represented by compound of formula (I) pharmaceutically acceptable salts and stereoisomers thereof. The present invention further provides the methods of preparation of compound of formula (I) and therapeutic uses thereof as anti-cancer agents.

XL 102

EXELIXIS AND AURIGENE ANNOUNCE THAT PROMISING PRECLINICAL DATA TO BE PRESENTED AT THE ENA SYMPOSIUM SUPPORT THE CLINICAL DEVELOPMENT OF A NOVEL CDK7 INHIBITOR

https://www.aurigene.com/exelixis-and-aurigene-announce-that-promising-preclinical-data-to-be-presented-at-the-ena-symposium-support-the-clinical-development-of-a-novel-cdk7-inhibitor/

Exelixis and Aurigene Announce That Promising Preclinical Data to Be Presented at the ENA Symposium Support the Clinical Development of a Novel CDK7 Inhibitor

– Detailed characterization of an oral inhibitor of CDK7 demonstrates potent activity against multiple hematologic and solid tumor cell lines, as monotherapy and in combination with chemotherapies –

October 09, 2020 03:02 AM Eastern Daylight Time

ALAMEDA, Calif.–(BUSINESS WIRE)–Exelixis, Inc. (Nasdaq: EXEL) and Aurigene Discovery Technologies Limited (Aurigene) today disclosed new preclinical data showing that AUR102 has potent anti-tumor activity in a large panel of cancer cell lines. AUR102 is a potent, selective, and orally bioavailable covalent inhibitor of cyclin-dependent kinase 7 (CDK7), which is an important regulator of the cellular transcriptional and cell cycle machinery. Exelixis has an exclusive option for AUR102 under its July 2019 exclusive collaboration, option and license agreement with Aurigene. The new data will be presented in a poster (Abstract 170) at the 32nd EORTC-NCI-AACR (ENA) Symposium, which is being held virtually on October 24-25, 2020.

“CDK7 plays a critical role in regulating cellular transcription and cell cycle machinery, making it an exciting target for cancer therapy”

“CDK7 plays a critical role in regulating cellular transcription and cell cycle machinery, making it an exciting target for cancer therapy,” said Murali Ramachandra, Ph.D., Chief Executive Officer of Aurigene. “The data to be presented at ENA 2020 demonstrate that AUR102 effectively engages CDK7 and inhibits a key mediator of the cell cycle and transcription. The ability to inhibit CDK7 activity with an orally available therapeutic such as AUR102 holds great potential to improve care and outcomes for patients with diverse cancer indications, including breast cancer, prostate cancer, leukemia and lymphoma.”

The abstract provides a summary of results from a detailed characterization of AUR102 in cancer cell lines and animal tumor models. Additional data will be presented in the poster. Key findings included in the abstract are:
• AUR102 exhibited potent anti-proliferative activity in a large panel of cell lines with induction of cell death in cell lines derived from multiple cancer types.
• The observed anti-proliferative activity correlated with cellular CDK7 target engagement and decreased levels of P-Ser5 RNAPII, a key mediator of transcription.
• AUR102 studies showed synergy when used in combination with multiple chemotherapies.
• Oral dosing with AUR102 resulted in dose-dependent anti-tumor activity, including complete tumor regression in diffuse large B-cell lymphoma, acute myeloid leukemia, and triple-negative breast cancer xenograft models.
• Inhibition of tumor growth was accompanied by complete target engagement as demonstrated in a parallel PK-PD study.
• AUR102 significantly impacts several pathways and key cancer driver and immune-response genes.

The study authors conclude that the data support clinical evaluation of AUR102 as a single agent and in combination with chemotherapies for the treatment of cancer.

“The exciting AUR102 data to be presented at ENA 2020 provide further validation of our partnering strategy, which gives us multiple opportunities to build a pipeline of best-in-class cancer therapies,” said Peter Lamb, Ph.D., Executive Vice President of Scientific Strategy and Chief Scientific Officer of Exelixis. “AUR102 could be the subject of an Investigational New Drug filing later this year, which would be an important value driver for the program itself and for our collaboration with Aurigene. We commend the Aurigene team on their ongoing success in building a robust body of data supporting the broad clinical potential of AUR102.”

Under the terms of the July 2019 agreement, Exelixis made an upfront payment of $10 million for exclusive options to license three preexisting programs from Aurigene. In addition, Exelixis and Aurigene initiated three Aurigene-led drug discovery programs on mutually agreed upon targets, in exchange for additional upfront option payments of $2.5 million per program. Exelixis is also contributing research funding to Aurigene to facilitate discovery and preclinical development work on all six programs. As the programs mature, Exelixis will have the opportunity to exercise an exclusive option for each program up until the time of Investigational New Drug (IND) filing acceptance. If Exelixis decides to exercise an option, it will make an option exercise payment to Aurigene and assume responsibility for that program’s future clinical development and commercialization including global manufacturing. Aurigene will be eligible for clinical development, regulatory, and sales milestones, as well as royalties on sales. Under the terms of the agreement, Aurigene retains limited development and commercial rights for India and Russia.

About Aurigene

Aurigene is a development stage biotech company engaged in discovery and clinical development of novel and best-in-class therapies to treat cancer and inflammatory diseases and a wholly owned subsidiary of Dr. Reddy’s Laboratories Ltd. (BSE: 500124, NSE: DRREDDY, NYSE: RDY). Aurigene is focused on precision-oncology, oral immune checkpoint inhibitors, and the Th-17 pathway. Aurigene’s programs currently in clinical development include an oral ROR-gamma inhibitor AUR101 for moderate to severe psoriasis in phase 2 under a U.S. FDA IND and a PD-L1/ VISTA antagonist CA-170 for non-squamous non-small cell lung cancer in phase 2b/3 in India. Additionally, Aurigene has multiple compounds at different stages of pre-clinical development. Aurigene has also partnered with several large and mid-pharma companies in the United States and Europe and has multiple programs in clinical development. For more information, please visit Aurigene’s website at http://www.aurigene.com.

About Exelixis

Founded in 1994, Exelixis, Inc. (Nasdaq: EXEL) is a commercially successful, oncology-focused biotechnology company that strives to accelerate the discovery, development and commercialization of new medicines for difficult-to-treat cancers. Following early work in model system genetics, we established a broad drug discovery and development platform that has served as the foundation for our continued efforts to bring new cancer therapies to patients in need. Our discovery efforts have resulted in four commercially available products, CABOMETYX® (cabozantinib), COMETRIQ® (cabozantinib), COTELLIC® (cobimetinib) and MINNEBRO® (esaxerenone), and we have entered into partnerships with leading pharmaceutical companies to bring these important medicines to patients worldwide. Supported by revenues from our marketed products and collaborations, we are committed to prudently reinvesting in our business to maximize the potential of our pipeline. We are supplementing our existing therapeutic assets with targeted business development activities and internal drug discovery – all to deliver the next generation of Exelixis medicines and help patients recover stronger and live longer. Exelixis is a member of Standard & Poor’s (S&P) MidCap 400 index, which measures the performance of profitable mid-sized companies. For more information about Exelixis, please visit http://www.exelixis.com, follow @ExelixisInc on Twitter or like Exelixis, Inc. on Facebook.

EXELIXIS AND AURIGENE ANNOUNCE THAT PROMISING PRECLINICAL DATA TO BE PRESENTED AT THE ENA SYMPOSIUM SUPPORT THE CLINICAL DEVELOPMENT OF A NOVEL CDK7 INHIBITOR

https://www.aurigene.com/exelixis-and-aurigene-announce-that-promising-preclinical-data-to-be-presented-at-the-ena-symposium-support-the-clinical-development-of-a-novel-cdk7-inhibitor/

Exelixis and Aurigene Announce That Promising Preclinical Data to Be Presented at the ENA Symposium Support the Clinical Development of a Novel CDK7 Inhibitor

– Detailed characterization of an oral inhibitor of CDK7 demonstrates potent activity against multiple hematologic and solid tumor cell lines, as monotherapy and in combination with chemotherapies –

October 09, 2020 03:02 AM Eastern Daylight Time

ALAMEDA, Calif.–(BUSINESS WIRE)–Exelixis, Inc. (Nasdaq: EXEL) and Aurigene Discovery Technologies Limited (Aurigene) today disclosed new preclinical data showing that AUR102 has potent anti-tumor activity in a large panel of cancer cell lines. AUR102 is a potent, selective, and orally bioavailable covalent inhibitor of cyclin-dependent kinase 7 (CDK7), which is an important regulator of the cellular transcriptional and cell cycle machinery. Exelixis has an exclusive option for AUR102 under its July 2019 exclusive collaboration, option and license agreement with Aurigene. The new data will be presented in a poster (Abstract 170) at the 32nd EORTC-NCI-AACR (ENA) Symposium, which is being held virtually on October 24-25, 2020.

“CDK7 plays a critical role in regulating cellular transcription and cell cycle machinery, making it an exciting target for cancer therapy”

“CDK7 plays a critical role in regulating cellular transcription and cell cycle machinery, making it an exciting target for cancer therapy,” said Murali Ramachandra, Ph.D., Chief Executive Officer of Aurigene. “The data to be presented at ENA 2020 demonstrate that AUR102 effectively engages CDK7 and inhibits a key mediator of the cell cycle and transcription. The ability to inhibit CDK7 activity with an orally available therapeutic such as AUR102 holds great potential to improve care and outcomes for patients with diverse cancer indications, including breast cancer, prostate cancer, leukemia and lymphoma.”

The abstract provides a summary of results from a detailed characterization of AUR102 in cancer cell lines and animal tumor models. Additional data will be presented in the poster. Key findings included in the abstract are:
• AUR102 exhibited potent anti-proliferative activity in a large panel of cell lines with induction of cell death in cell lines derived from multiple cancer types.
• The observed anti-proliferative activity correlated with cellular CDK7 target engagement and decreased levels of P-Ser5 RNAPII, a key mediator of transcription.
• AUR102 studies showed synergy when used in combination with multiple chemotherapies.
• Oral dosing with AUR102 resulted in dose-dependent anti-tumor activity, including complete tumor regression in diffuse large B-cell lymphoma, acute myeloid leukemia, and triple-negative breast cancer xenograft models.
• Inhibition of tumor growth was accompanied by complete target engagement as demonstrated in a parallel PK-PD study.
• AUR102 significantly impacts several pathways and key cancer driver and immune-response genes.

The study authors conclude that the data support clinical evaluation of AUR102 as a single agent and in combination with chemotherapies for the treatment of cancer.

“The exciting AUR102 data to be presented at ENA 2020 provide further validation of our partnering strategy, which gives us multiple opportunities to build a pipeline of best-in-class cancer therapies,” said Peter Lamb, Ph.D., Executive Vice President of Scientific Strategy and Chief Scientific Officer of Exelixis. “AUR102 could be the subject of an Investigational New Drug filing later this year, which would be an important value driver for the program itself and for our collaboration with Aurigene. We commend the Aurigene team on their ongoing success in building a robust body of data supporting the broad clinical potential of AUR102.”

Under the terms of the July 2019 agreement, Exelixis made an upfront payment of $10 million for exclusive options to license three preexisting programs from Aurigene. In addition, Exelixis and Aurigene initiated three Aurigene-led drug discovery programs on mutually agreed upon targets, in exchange for additional upfront option payments of $2.5 million per program. Exelixis is also contributing research funding to Aurigene to facilitate discovery and preclinical development work on all six programs. As the programs mature, Exelixis will have the opportunity to exercise an exclusive option for each program up until the time of Investigational New Drug (IND) filing acceptance. If Exelixis decides to exercise an option, it will make an option exercise payment to Aurigene and assume responsibility for that program’s future clinical development and commercialization including global manufacturing. Aurigene will be eligible for clinical development, regulatory, and sales milestones, as well as royalties on sales. Under the terms of the agreement, Aurigene retains limited development and commercial rights for India and Russia.

About Aurigene

Aurigene is a development stage biotech company engaged in discovery and clinical development of novel and best-in-class therapies to treat cancer and inflammatory diseases and a wholly owned subsidiary of Dr. Reddy’s Laboratories Ltd. (BSE: 500124, NSE: DRREDDY, NYSE: RDY). Aurigene is focused on precision-oncology, oral immune checkpoint inhibitors, and the Th-17 pathway. Aurigene’s programs currently in clinical development include an oral ROR-gamma inhibitor AUR101 for moderate to severe psoriasis in phase 2 under a U.S. FDA IND and a PD-L1/ VISTA antagonist CA-170 for non-squamous non-small cell lung cancer in phase 2b/3 in India. Additionally, Aurigene has multiple compounds at different stages of pre-clinical development. Aurigene has also partnered with several large and mid-pharma companies in the United States and Europe and has multiple programs in clinical development. For more information, please visit Aurigene’s website at http://www.aurigene.com.

About Exelixis

Founded in 1994, Exelixis, Inc. (Nasdaq: EXEL) is a commercially successful, oncology-focused biotechnology company that strives to accelerate the discovery, development and commercialization of new medicines for difficult-to-treat cancers. Following early work in model system genetics, we established a broad drug discovery and development platform that has served as the foundation for our continued efforts to bring new cancer therapies to patients in need. Our discovery efforts have resulted in four commercially available products, CABOMETYX® (cabozantinib), COMETRIQ® (cabozantinib), COTELLIC® (cobimetinib) and MINNEBRO® (esaxerenone), and we have entered into partnerships with leading pharmaceutical companies to bring these important medicines to patients worldwide. Supported by revenues from our marketed products and collaborations, we are committed to prudently reinvesting in our business to maximize the potential of our pipeline. We are supplementing our existing therapeutic assets with targeted business development activities and internal drug discovery – all to deliver the next generation of Exelixis medicines and help patients recover stronger and live longer. Exelixis is a member of Standard & Poor’s (S&P) MidCap 400 index, which measures the performance of profitable mid-sized companies. For more information about Exelixis, please visit http://www.exelixis.com, follow @ExelixisInc on Twitter or like Exelixis, Inc. on Facebook.

Exelixis Forward-Looking Statements

This press release contains forward-looking statements, including, without limitation, statements related to: Exelixis’ and Aurigene’s plans to present preclinical data in support of the continued development of AUR102 in a poster as part of the 32nd ENA Symposium; the potential for AUR102 to improve care and outcomes for patients with diverse cancer indications, including breast cancer, prostate cancer, leukemia and lymphoma; the potential for AUR102 to be the subject of an Investigational New Drug filing later in 2020; Exelixis’ potential future financial and other obligations under the exclusive collaboration, option and license agreement with Aurigene; and Exelixis’ plans to reinvest in its business to maximize the potential of the company’s pipeline, including through targeted business development activities and internal drug discovery. Any statements that refer to expectations, projections or other characterizations of future events or circumstances are forward-looking statements and are based upon Exelixis’ current plans, assumptions, beliefs, expectations, estimates and projections. Forward-looking statements involve risks and uncertainties. Actual results and the timing of events could differ materially from those anticipated in the forward-looking statements as a result of these risks and uncertainties, which include, without limitation: the availability of data at the referenced times; the level of costs associated with Exelixis’ commercialization, research and development, in-licensing or acquisition of product candidates, and other activities; uncertainties inherent in the drug discovery and product development process; Exelixis’ dependence on its relationship with Aurigene, including Aurigene’s adherence to its obligations under the exclusive collaboration, option and license agreement and the level of Aurigene’s assistance to Exelixis in completing clinical trials, pursuing regulatory approvals or successfully commercializing partnered compounds in the territories where they may be approved; the continuing COVID-19 pandemic and its impact on Exelixis’ research and development operations; complexities and the unpredictability of the regulatory review and approval processes in the U.S. and elsewhere; Exelixis’ and Aurigene’s continuing compliance with applicable legal and regulatory requirements; Exelixis’ and Aurigene’s ability to protect their respective intellectual property rights; market competition; changes in economic and business conditions; and other factors affecting Exelixis and its product pipeline discussed under the caption “Risk Factors” in Exelixis’ Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) on August 6, 2020, and in Exelixis’ future filings with the SEC. All forward-looking statements in this press release are based on information available to Exelixis as of the date of this press release, and Exelixis undertakes no obligation to update or revise any forward-looking statements contained herein, except as required by law.

Exelixis, the Exelixis logo, CABOMETYX, COMETRIQ and COTELLIC are registered U.S. trademarks. MINNEBRO is a registered Japanese trademark.

Lenalidomide hydrate,


2D chemical structure of 847871-99-2
LENALIDOMIDE HEMIHYDRATE
Lenalidomide enantiomers.svg

Lenalidomide hydrate

レナリドミド水和物

An immunomodulator.

CC-5013 hemihydrate

2,6-Piperidinedione, 3-(4-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-, hydrate (2:1)

(+/-)-2,6-Piperidinedione, 3-(4-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-, hydrate (2:1)

Formula(C13H13N3O3)2. H2O
CAS847871-99-2
Mol weight536.5365

EMA APPROVED 2021/2/11,  Lenalidomide KRKA

Research Code:CDC-501; CC-5013

Trade Name:Revlimid®

MOA:Angiogenesis inhibitor

Indication:Myelodysplastic syndrome (MDS); Mantle cell lymphoma (MCL); Multiple myeloma (MM)

Status:Approved

Company:Celgene (Originator)

Sales:$5,801.1 Million (Y2015); 
$4,980 Million (Y2014);;
$4280 Million (Y2013);;
$3766.6 Million (Y2012);;
$3208.2 Million (Y2011);ATC Code:L04AX04

Approval DateApproval TypeTrade NameIndicationDosage FormStrengthCompanyReview Classification
2005-12-27Marketing approvalRevlimidMultiple myeloma (MM),Myelodysplastic syndrome (MDS),Mantle cell lymphoma (MCL)Capsule2.5 mg/5 mg/10 mg/15 mg/20 mg/25 mgCelgenePriority; Orphan

More

Approval DateApproval TypeTrade NameIndicationDosage FormStrengthCompanyReview Classification
2007-06-14Marketing approvalRevlimidMultiple myeloma (MM),Myelodysplastic syndrome (MDS)Capsule2.5 mg/5 mg/7.5 mg/10 mg/15 mg/20 mg/25 mgCelgeneOrphan

More

Approval DateApproval TypeTrade NameIndicationDosage FormStrengthCompanyReview Classification
2010-08-20New indicationRevlimidMyelodysplastic syndrome (MDS)Capsule5 mgCelgene 
2010-06-25Marketing approvalRevlimidMultiple myeloma (MM)Capsule5 mgCelgene 

More

Approval DateApproval TypeTrade NameIndicationDosage FormStrengthCompanyReview Classification
2013-01-23Marketing approval瑞复美/RevlimidMultiple myeloma (MM)Capsule5 mgCelgene 
2013-01-23Marketing approval瑞复美/RevlimidMultiple myeloma (MM)Capsule10 mgCelgene 
2013-01-23Marketing approval瑞复美/RevlimidMultiple myeloma (MM)Capsule15 mgCelgene 
2013-01-23Marketing approval瑞复美/RevlimidMultiple myeloma (MM)Capsule25 mgCelgene
Molecular Weight259.26
FormulaC13H13N3O3
CAS No.191732-72-6 (Lenalidomide);
Chemical Name3(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione

Lenalidomide was first approved by the U.S. Food and Drug Administration (FDA) on Dec 27, 2005, then approved by European Medicine Agency (EMA) on June 14, 2007, and approved by Pharmaceuticals and Medical Devices Agency of Japan (PMDA) on June 25, 2010. It was developed and marketed as Revlimid® by Celgene.

Lenalidomide is an analogue of thalidomide with immunomodulatory, antiangiogenic, and antineoplastic properties. In multiple myeloma cells, the combination of lenalidomide and dexamethasone synergizes the inhibition of cell proliferation and the induction of apoptosis. Revlimid® is indicated for the treatment of multiple myeloma (MM), in combination with dexamethasone, in patients who have received at least one prior therapy, transfusion-dependent anemia due to low-or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q abnormality with or without additional cytogenetic abnormalities and mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib.

Revlimid® is available as capsule for oral use, containing 2.5, 5, 10, 15, 20 or 25 mg of free Lenalidomide. The recommended dose is 25 mg once daily for multiple myeloma (MM), in combination with 40 mg dexamethasone once daily, 10 mg once daily for myelodysplastic syndromes (MDS) and 25 mg once daily for mantle cell lymphoma (MCL).

Lenalidomide, sold under the trade name Revlimid among others, is a medication used to treat multiple myeloma (MM) and myelodysplastic syndromes (MDS).[2] For MM it is used after at least one other treatment and generally together with dexamethasone.[2] It is taken by mouth.[2]

Common side effects include diarrhea, itchiness, joint pain, fever, headache, and trouble sleeping.[2] Severe side effects may include low blood plateletslow white blood cells, and blood clots.[2] Use during pregnancy may harm the baby.[2] The dose may need to be adjusted in people with kidney problems.[2] It has a chemical structure similar to thalidomide but has a different mechanism of action.[3][2] How it works is not entirely clear as of 2019.[2]

Lenalidomide was approved for medical use in the United States in 2005.[2] It is on the World Health Organization’s List of Essential Medicines.[4]

Medical uses

Multiple myeloma

Lenalidomide is used to treat multiple myeloma.[5] It is a more potent molecular analog of thalidomide, which inhibits tumor angiogenesis, tumor-secreted cytokines, and tumor proliferation through induction of apoptosis.[6][7][8]

Lenalidomide is effective at inducing a complete or “very good partial” response and improves progression-free survival. Adverse events more common in people receiving lenalidomide for myeloma include neutropeniadeep vein thrombosisinfections, and an increased risk of other hematological malignancies.[9] The risk of second primary hematological malignancies does not outweigh the benefit of using lenalidomide in relapsed or refractory multiple myeloma.[10] It may be more difficult to mobilize stem cells for autograft in people who have received lenalidomide.[6]

In 2006, lenalidomide received U.S. Food and Drug Administration (FDA) clearance for use in combination with dexamethasone in people with multiple myeloma who have received at least one prior therapy.[11] In 2017, the FDA approved lenalidomide as standalone maintenance therapy (without dexamethasone) for people with multiple myeloma following autologous stem cell transplant.[12]

In 2009, The National Institute for Health and Clinical Excellence issued a final appraisal determination approving lenalidomide in combination with dexamethasone as an option to treat people with multiple myeloma who have received two or more prior therapies in England and Wales.[13]

The use of lenalidomide combined with other drugs was evaluated. It was seen that the drug combinations of lenalidomide plus dexamethasone and continuous bortezomib plus lenalidomide plus dexamethasone probably result in an increase of the overall survival.[14]

Myelodysplastic syndromes

Lenalidomide was approved by the FDA on 27 December 2005 for patients with low- or intermediate-1-risk myelodysplastic syndromes who have chromosome 5q deletion syndrome (5q- syndrome) with or without additional cytogenetic abnormalities.[15][16][17] It was approved on 17 June 2013 by the European Medicines Agency for use in patients with low- or intermediate-1-risk myelodysplastic syndromes who have 5q- deletion syndrome but no other cytogenetic abnormalities and are dependent on red blood cell transfusions, for whom other treatment options have been found to be insufficient or inadequate.[18]

Mantle cell lymphoma

Lenalidomide is approved by FDA as a specialty drug requiring a specialty pharmacy distribution for mantle cell lymphoma in patients whose disease has relapsed or progressed after at least two prior therapies, one of which must have included the medicine bortezomib.[3]

Amyloidosis

Although not specifically approved by the FDA for use in treating amyloidosis, Lenalidomide is widely used in the treatment of that condition, often in combination with dexamethasone. [19]

Adverse effects

In addition to embryo-fetal toxicity, lenalidomide carries black box warnings for hematologic toxicity (including neutropenia and thrombocytopenia) and thromboembolism.[3] Serious potential side effects include thrombosispulmonary embolushepatotoxicity, and bone marrow toxicity resulting in neutropenia and thrombocytopenia. Myelosuppression is the major dose-limiting toxicity, which is not the case with thalidomide.[20]

Lenalidomide may be associated with such adverse effects as second primary malignancy, severe cutaneous reactions, hypersensitivity reactionstumor lysis syndrome, tumor flare reaction, hypothyroidism, and hyperthyroidism.[3]

Teratogenicity

Lenalidomide is related to thalidomide, which is known to be teratogenic. Tests in monkeys suggest that lenalidomide is likewise teratogenic.[21] It cannot be prescribed for women who are pregnant or who may become pregnant during therapy.[1] For this reason, the drug is only available in the United States through a restricted distribution system in conjunction with a risk evaluation and mitigation strategy. Females who may become pregnant must use at least two forms of reliable contraception during treatment and for at least four weeks after discontinuing treatment with lenalidomide.[3][22]

Venous thromboembolism

Lenalidomide, like its parent compound thalidomide, may cause venous thromboembolism (VTE), a potentially serious complication with their use. High rates of VTE have been found in patients with multiple myeloma who received thalidomide or lenalidomide in conjunction with dexamethasonemelphalan, or doxorubicin.[23]

Stevens-Johnson syndrome

In March 2008, the U.S. Food and Drug Administration (FDA) included lenalidomide on a list of twenty prescription drugs under investigation for potential safety problems. The drug was investigated for possibly increasing the risk of developing Stevens–Johnson syndrome, a life-threatening skin condition.[24]

FDA ongoing safety review

In 2011, the FDA initiated an ongoing review of clinical trials that found an increased risk of developing cancers such as acute myelogenous leukemia and B-cell lymphoma,[25] though it did not advise patients to discontinue treatment with lenalidomide.[26]

Mechanism of action

Lenalidomide has been used to successfully treat both inflammatory disorders and cancers in the past ten years.[when?] There are multiple mechanisms of action, and they can be simplified by organizing them as mechanisms of action in vitro and in vivo.[27] In vitro, lenalidomide has three main activities: direct anti-tumor effect, inhibition of angiogenesis, and immunomodulationIn vivo, lenalidomide induces tumor cell apoptosis directly and indirectly by inhibition of bone marrow stromal cell support, by anti-angiogenic and anti-osteoclastogenic effects, and by immunomodulatory activity. Lenalidomide has a broad range of activities that can be exploited to treat many hematologic and solid cancers.

On a molecular level, lenalidomide has been shown to interact with the ubiquitin E3 ligase cereblon[28] and target this enzyme to degrade the Ikaros transcription factors IKZF1 and IKZF3.[29] This mechanism was unexpected as it suggests that the major action of lenalidomide is to re-target the activity of an enzyme rather than block the activity of an enzyme or signaling process, and thereby represents a novel mode of drug action. A more specific implication of this mechanism is that the teratogenic and anti-neoplastic properties of lenalidomide, and perhaps other thalidomide derivatives, could be disassociated.

History

See also: Development of analogs of thalidomide

Lenalidomide was approved for medical use in the United States in 2005.[2]

Society and culture

Economics

Lenalidomide costs US$163,381 per year for the average person in the United States as of 2012.[25] Lenalidomide made almost $9.7bn for Celgene in 2018.[30]

In 2013, the UK National Institute for Health and Care Excellence (NICE) rejected lenalidomide for “use in the treatment of people with a specific type of the bone marrow disorder myelodysplastic syndrome (MDS)” in England and Scotland, arguing that Celgene “did not provide enough evidence to justify the GB£3,780 per month (US$5,746.73) price-tag of lenalidomide for use in the treatment of people with a specific type of the bone marrow disorder myelodysplastic syndrome (MDS)”.[31]

Research

Lenalidomide is undergoing clinical trial as a treatment for Hodgkin’s lymphoma,[32] as well as non-Hodgkin’s lymphomachronic lymphocytic leukemia and solid tumor cancers, such as carcinoma of the pancreas.[33] One Phase III clinical trial being conducted by Celgene in elderly patients with B-cell chronic lymphocytic leukemia was halted in July 2013, when a disproportionate number of cancer deaths were observed during treatment with lenalidomide versus patients treated with chlorambucil.[34]

SynRoute 1
Reference:

1. WO9803502A1 / US2002173658A1.

2. Bioorg. Med. Chem. Lett. 19999, 1625-1630.Route 2
Reference:

1. WO2010139266A1 / US2012077982A1.Route 3
Reference:

1. CN103497175A.Route 4
Reference:

1. WO2010139266A1 / US2012077982A1.Route 5
Reference:

1. CN103554082A.

Clip

Alternative synthesis of lenalidomide | SpringerLink

SYN

File:Lenalidomide synthesis.png - Wikimedia Commons

SCALABLE AND GREEN PROCESS FOR THE SYNTHESIS OF ANTICANCER DRUG LENALIDOMIDE

Yuri Ponomaryov, Valeria Krasikova, Anton Lebedev, Dmitri Chernyak, Larisa Varacheva, Alexandr Chernobroviy

Cover Image

Abstract

A new process for the synthesis of anticancer drug lenalidomide was developed, using platinum group metal-free and efficient reduction of nitro group with the iron powder and ammonium chloride. It was found that the bromination of the key raw material, methyl 2-methyl-3-nitrobenzoate, could be carried out in chlorine-free solvent methyl acetate without forming significant amounts of hazardous by-products. We also have compared the known synthetic methods for cyclization of methyl 2-(bromomethyl)-3-nitrobenzoate and 3-aminopiperidinedione to form lenalidomide nitro precursor.

How to Cite
Ponomaryov, Y.; Krasikova, V.; Lebedev, A.; Chernyak, D.; Varacheva, L.; Chernobroviy, A. Chem. Heterocycl. Compd. 201551, 133. [Khim. Geterotsikl. Soedin. 201551, 133.]

For this article in the English edition see DOI 10.1007/s10593-015-1670-0

SYN

https://link.springer.com/article/10.1007/s10593-015-1670-0

A new process for the synthesis of anticancer drug lenalidomide was developed, using platinum group metal-free and efficient reduction of nitro group with the iron powder and ammonium chloride. It was found that the bromination of the key raw material, methyl 2-methyl-3-nitrobenzoate, could be carried out in chlorine-free solvent methyl acetate without forming significant amounts of hazardous by-products. We also have compared the known synthetic methods for cyclization of methyl 2-(bromomethyl)-3-nitrobenzoate and 3-aminopiperidinedione to form lenalidomide nitro precursor.

SYN

File:Lenalidomide synthesis.png

SYN

EP 0925294; US 5635517; WO 9803502

Cyclization of N-(benzyloxycarbonyl)glutamine (I) by means of CDI in refluxing THF gives 3-(benzyloxycarbonylamino)piperidine-2,6-dione (II), which is deprotected with H2 over Pd/C in ethyl acetate/4N HCl to yield 3-aminopiperidine-2,6-dione hydrochloride (III). Bromination of 2-methyl-3-nitrobenzoic acid methyl ester (IV) with NBS in CCl4 provides 2-(bromomethyl)-3-nitrobenzoic acid methyl ester (V), which is cyclized with the aminopiperidine (III) by means of triethylamine in hot DMF to afford 3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (VI). Finally, the nitro group of compound (VI) is reduced with H2 over Pd/C in methanol (1, 2).

SYN

Bioorg Med Chem Lett 1999,9(11),1625

Treatment of 3-nitrophthalimide (I) with ethyl chloroformate and triethylamine produced 3-nitro-N-(ethoxycarbonyl)phthalimide (II), which was condensed with L-glutamine tert-butyl ester hydrochloride (III) to afford the phthaloyl glutamine derivative (IV). Acidic cleavage of the tert-butyl ester of (IV) provided the corresponding carboxylic acid (V). This was cyclized to the required glutarimide (VI) upon treatment with thionyl chloride and then with triethylamine. The nitro group of (VI) was finally reduced to amine by hydrogenation over Pd/C.

Lenalidomide

  • Synonyms:CC-5013, CDC 501
  • ATC:L04AX04
  • MW:259.27 g/mol
  • CAS-RN:191732-72-6
  • InChI Key:GOTYRUGSSMKFNF-JTQLQIEISA-N
  • InChI:InChI=1S/C13H13N3O3/c14-9-3-1-2-7-8(9)6-16(13(7)19)10-4-5-11(17)15-12(10)18/h1-3,10H,4-6,14H2,(H,15,17,18)/t10-/m0/s1

Synthesis

References

  1. Jump up to:a b c “Lenalidomide (Revlimid) Use During Pregnancy”Drugs.com. 13 March 2020. Retrieved 13 August 2020.
  2. Jump up to:a b c d e f g h i j k “Lenalidomide Monograph for Professionals”Drugs.com. Retrieved 27 October 2019.
  3. Jump up to:a b c d e “DailyMed – Revlimid- lenalidomide capsule”dailymed.nlm.nih.gov. Retrieved 27 October 2019.
  4. ^ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  5. ^ Armoiry X, Aulagner G, Facon T (June 2008). “Lenalidomide in the treatment of multiple myeloma: a review”Journal of Clinical Pharmacy and Therapeutics33 (3): 219–26. doi:10.1111/j.1365-2710.2008.00920.xPMID 18452408S2CID 1228171.
  6. Jump up to:a b Li S, Gill N, Lentzsch S (November 2010). “Recent advances of IMiDs in cancer therapy”. Current Opinion in Oncology22 (6): 579–85. doi:10.1097/CCO.0b013e32833d752cPMID 20689431S2CID 205547603.
  7. ^ Tageja N (March 2011). “Lenalidomide – current understanding of mechanistic properties”. Anti-Cancer Agents in Medicinal Chemistry11 (3): 315–26. doi:10.2174/187152011795347487PMID 21426296.
  8. ^ Kotla V, Goel S, Nischal S, Heuck C, Vivek K, Das B, Verma A (August 2009). “Mechanism of action of lenalidomide in hematological malignancies”Journal of Hematology & Oncology2: 36. doi:10.1186/1756-8722-2-36PMC 2736171PMID 19674465.
  9. ^ Yang B, Yu RL, Chi XH, Lu XC (2013). “Lenalidomide treatment for multiple myeloma: systematic review and meta-analysis of randomized controlled trials”PLOS ONE8 (5): e64354. Bibcode:2013PLoSO…864354Ydoi:10.1371/journal.pone.0064354PMC 3653900PMID 23691202.
  10. ^ Dimopoulos MA, Richardson PG, Brandenburg N, Yu Z, Weber DM, Niesvizky R, Morgan GJ (March 2012). “A review of second primary malignancy in patients with relapsed or refractory multiple myeloma treated with lenalidomide”Blood119 (12): 2764–7. doi:10.1182/blood-2011-08-373514PMID 22323483.
  11. ^ “FDA approves lenalidomide oral capsules (Revlimid) for use in combination with dexamethasone in patients with multiple myeloma”Food and Drug Administration (FDA). 29 June 2006. Retrieved 15 October 2015.[dead link]
  12. ^ “Lenalidomide (Revlimid)”Food and Drug Administration(FDA). 22 February 2017.
  13. ^ “REVLIMID Receives Positive Final Appraisal Determination from National Institute for Health and Clinical Excellence (NICE) for Use in the National Health Service (NHS) in England and Wales”Reuters. 23 April 2009.
  14. ^ Piechotta V, Jakob T, Langer P, Monsef I, Scheid C, Estcourt LJ, et al. (Cochrane Haematology Group) (November 2019). “Multiple drug combinations of bortezomib, lenalidomide, and thalidomide for first-line treatment in adults with transplant-ineligible multiple myeloma: a network meta-analysis”The Cochrane Database of Systematic Reviews2019 (11). doi:10.1002/14651858.CD013487PMC 6876545PMID 31765002.
  15. ^ List A, Kurtin S, Roe DJ, Buresh A, Mahadevan D, Fuchs D, et al. (February 2005). “Efficacy of lenalidomide in myelodysplastic syndromes”. The New England Journal of Medicine352 (6): 549–57. doi:10.1056/NEJMoa041668PMID 15703420.
  16. ^ List AF (August 2005). “Emerging data on IMiDs in the treatment of myelodysplastic syndromes (MDS)”. Seminars in Oncology32 (4 Suppl 5): S31-5. doi:10.1053/j.seminoncol.2005.06.020PMID 16085015.
  17. ^ List A, Dewald G, Bennett J, Giagounidis A, Raza A, Feldman E, et al. (October 2006). “Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion”. The New England Journal of Medicine355 (14): 1456–65. doi:10.1056/NEJMoa061292PMID 17021321.
  18. ^ “Revlimid Approved In Europe For Use In Myelodysplastic Syndromes”. The MDS Beacon. Retrieved 17 June 2013.
  19. ^ “Revlimid and Amyloidosis AL” (PDF). MyelomaUK. Retrieved 3 October 2020.
  20. ^ Rao KV (September 2007). “Lenalidomide in the treatment of multiple myeloma”. American Journal of Health-System Pharmacy64 (17): 1799–807. doi:10.2146/ajhp070029PMID 17724360.
  21. ^ “Revlimid Summary of Product Characteristics. Annex I” (PDF). European Medicines Agency. 2012. p. 6.
  22. ^ Ness, Stacey (13 March 2014). “New Specialty Drugs”. Pharmacy Times. Retrieved 5 November 2015.
  23. ^ Bennett CL, Angelotta C, Yarnold PR, Evens AM, Zonder JA, Raisch DW, Richardson P (December 2006). “Thalidomide- and lenalidomide-associated thromboembolism among patients with cancer”. JAMA296 (21): 2558–60. doi:10.1001/jama.296.21.2558-cPMID 17148721.
  24. ^ “Potential Signals of Serious Risks/New Safety Information Identified from the Adverse Event Reporting System (AERS) between January – March 2008”Food and Drug Administration(FDA). March 2008. Archived from the original on 19 April 2014. Retrieved 16 December 2019.
  25. Jump up to:a b Badros AZ (May 2012). “Lenalidomide in myeloma–a high-maintenance friend”. The New England Journal of Medicine366(19): 1836–8. doi:10.1056/NEJMe1202819PMID 22571206.
  26. ^ “FDA Drug Safety Communication: Ongoing safety review of Revlimid (lenalidomide) and possible increased risk of developing new malignancies”Food and Drug Administration (FDA). April 2011.
  27. ^ Vallet S, Palumbo A, Raje N, Boccadoro M, Anderson KC (July 2008). “Thalidomide and lenalidomide: Mechanism-based potential drug combinations”. Leukemia & Lymphoma49 (7): 1238–45. doi:10.1080/10428190802005191PMID 18452080S2CID 43350339.
  28. ^ Zhu YX, Braggio E, Shi CX, Bruins LA, Schmidt JE, Van Wier S, et al. (November 2011). “Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide”Blood118 (18): 4771–9. doi:10.1182/blood-2011-05-356063PMC 3208291PMID 21860026.
  29. ^ Stewart AK (January 2014). “Medicine. How thalidomide works against cancer”Science343 (6168): 256–7. doi:10.1126/science.1249543PMC 4084783PMID 24436409.
  30. ^ “Top 10 Best-Selling Cancer Drugs of 2018”. Genetic Engineering and Biotechnology News. 22 April 2019. Retrieved 25 April 2019.
  31. ^ “Revlimid faces NICE rejection for use in rare blood cancer Watchdog’s draft guidance does not recommend Celgene’s drug for NHS use in England and Wales”. Pharma News. 11 July 2013. Retrieved 5 November 2015.
  32. ^ “Phase II Study of Lenalidomide for the Treatment of Relapsed or Refractory Hodgkin’s Lymphoma”ClinicalTrials.gov. US National Institutes of Health. February 2009.
  33. ^ “276 current clinical trials world-wide, both recruiting and fully enrolled, as of 27 February 2009”ClinicalTrials.gov. US National Institutes of Health. February 2009.
  34. ^ “Celgene Discontinues Phase 3 Revlimid Study after ‘Imbalance’ of Deaths”. Nasdaq. 18 July 2013.

External links[edit]

Clinical data
Pronunciation/ˌlɛnəˈlɪdoʊmaɪd/
Trade namesRevlimid, Linamide, others
AHFS/Drugs.comMonograph
MedlinePlusa608001
License dataEU EMAby INNUS DailyMedLenalidomide
Pregnancy
category
AU: X (High risk)[1]
Routes of
administration
By mouth (capsules)
ATC codeL04AX04 (WHO)
Legal status
Legal statusAU: S4 (Prescription only)UK: POM (Prescription only)US: ℞-onlyEU: Rx-only
Pharmacokinetic data
BioavailabilityUndetermined
Protein binding30%
MetabolismUndetermined
Elimination half-life3 hours
ExcretionKidney (67% unchanged)
Identifiers
showIUPAC name
CAS Number191732-72-6 
PubChem CID216326
IUPHAR/BPS7331
DrugBankDB00480 
ChemSpider187515 
UNIIF0P408N6V4
KEGGD04687 
ChEMBLChEMBL848 
CompTox Dashboard (EPA)DTXSID8046664 
ECHA InfoCard100.218.924 
Chemical and physical data
FormulaC13H13N3O3
Molar mass259.265 g·mol−1
3D model (JSmol)Interactive image
ChiralityRacemic mixture
hideSMILESO=C1NC(=O)CCC1N3C(=O)c2cccc(c2C3)N
hideInChIInChI=1S/C13H13N3O3/c14-9-3-1-2-7-8(9)6-16(13(7)19)10-4-5-11(17)15-12(10)18/h1-3,10H,4-6,14H2,(H,15,17,18) Key:GOTYRUGSSMKFNF-UHFFFAOYSA-N 

//////////Lenalidomide hydrate, Lenalidomide KRKA, EU 2021, APPROVALS 2021, レナリドミド水和物 , CC-5013 hemihydrate,

#Lenalidomide hydrate, #Lenalidomide KRKA, #EU 2021, #APPROVALS 2021, #レナリドミド水和物 , #CC-5013 hemihydrate,

O.Nc1cccc2C(=O)N(Cc12)C3CCC(=O)NC3=O.Nc4cccc5C(=O)N(Cc45)C6CCC(=O)NC6=O

Lurbinectedin


Lurbinectedin.png

Lurbinectedin

(1’R,6R,6aR,7R,13S,14S,16R)-5-(Acetyloxy)-2′,3′,4′,6,6a,7,9′-decahydro-8,14-dihydroxy-6′,9-dimethoxy-4,10,23-trimethyl-spiro(6,16-(epithiopropaneoxymethano)-7.13-imino-12H-1,3-dioxolo[7,8]soquino[3,2-b][3]benzazocine-20,1′-[1H]pyrido[3,4-b]indol]-19-one

Molecular Weight784.87
FormulaC41H44N4O10S
CAS No.497871-47-3 (Lurbinectedin);
Chemical NameSpiro[6,16-(epithiopropanoxymethano)-7,13-imino-12H-1,3-dioxolo[7,8]isoquino[3,2-b][3]benzazocine-20,1′-[1H]pyrido[3,4-b]indol]-19-one, 5-(acetyloxy)-2′,3′,4′,6,6a,7,9′,13,14,16-decahydro-8,14-dihydroxy-6′,9-dimethoxy-4,10,23-trimethyl-, (1’R,6R,6aR,7R,13S,14S,16R)- (9CI)

fda approved , 6/15/2020 , ZEPZELCA, Pharma Mar S.A.

To treat metastatic small cell lung cancer
Drug Trials Snapshot

Research Code:PM-01183; PM-1183

MOA:RNA polymerase inhibitor

Indication:Ovarian cancer; Breast cancer; Non small cell lung cancer (NSCLC)лурбинектединلوربينيكتيدين芦比替定(1R,1’R,2’R,3’R,11’S,12’S,14’R)-5′,12′-Dihydroxy-6,6′-dimethoxy-7′,21′,30′-trimethyl-27′-oxo-2,3,4,9-tetrahydrospiro[β-carboline-1,26′-[17,19,28]trioxa[24]thia[13,30]diazaheptacyclo[12.9.6.13,11. 02,13.04,9.015,23.016,20]triaconta[4,6,8,15,20,22]hexaen]-22′-yl acetate [ACD/IUPAC Name]2CN60TN6ZS497871-47-3[RN]9397

Lurbinectedin is in phase III clinical development for the treatment of platinum refractory/resistant ovarian cancer.

Phase II clinical trials are also ongoing for several oncology indications: non-small cell lung cancer, breast cancer, small cell lung cancer, head and neck carcinoma, neuroendocrine tumors, biliary tract carcinoma, endometrial carcinoma, germ cell tumors and Ewing’s family of tumors.

Lurbinectedin, sold under the brand name Zepzelca, is a medication for the treatment of adults with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy.[1][2][3]

The most common side effects include leukopenia, lymphopenia, fatigue, anemia, neutropenia, increased creatinine, increased alanine aminotransferase, increased glucose, thrombocytopenia, nausea, decreased appetite, musculoskeletal pain, decreased albumin, constipation, dyspnea, decreased sodium, increased aspartate aminotransferase, vomiting, cough, decreased magnesium and diarrhea.[1][2][3]

Lurbinectedin is a synthetic tetrahydropyrrolo [4, 3, 2-de]quinolin-8(1H)-one alkaloid analogue with potential antineoplastic activity.[4] Lurbinectedin covalently binds to residues lying in the minor groove of DNA, which may result in delayed progression through S phase, cell cycle arrest in the G2/M phase and cell death.[4]

Lurbinectedin was approved for medical use in the United States in June 2020.[5][1][2][3][6]

Structure

Lurbinectedin is structurally similar to trabectedin, although the tetrahydroisoquinoline present in trabectedin is replaced with a tetrahydro β-carboline which enables lurbinectedin to exhibit increased antitumor activity compared with trabectedin.[7]

Biosynthesis

Lurbinectedin a marine agent isolated from the sea squirt species Ecteinascidia turbinata. Synthetic production is necessary because very small amounts can be obtained from sea organisms. For example, one ton (1000 kg) of sea squirts are required to produce one gram of trabectedin, which is analogue of lurbinectedin. Complex synthesis of lurbinectedin starts from small, common starting materials that require twenty-six individual steps to produce the drug with overall yield of 1.6%.[8][9]

Mechanism of action

According to PharmaMar,[10] lurbinectedin inhibits the active transcription of the encoding genes. This has two consequences. On one hand, it promotes tumor cell death, and on the other it normalizes tumor microenvironment. Active transcription is the process by which there are specific signal where information contained in the DNA sequence is transferred to an RNA molecule. This activity depends on the activity of an enzyme called RNA polymerase II. Lurbinectedin inhibits transcription through a very precise mechanism. Firstly, lurbinectedin binds to specific DNA sequences. It is at these precise spots that slides down the DNA to produce RNA polymerase II that is blocked and degraded by lurbinectedin. Lurbinectedin also has important role in tumor microenvironment. The tumor cells act upon macrophages to avoid them from behaving like an activator of the immune system. Literally, macrophages work in any tumor’s favor. Macrophages can contribute to tumor growth and progression by promoting tumor cell proliferation and invasion, fostering tumor angiogenesis and suppressing antitumor immune cells.[11][12] Attracted to oxygen-starved (hypoxic) and necrotic tumor cells they promote chronic inflammation. So, not only that macrophages inhibit immune system avoiding the destruction of tumor cells, but they also create tumor tissue that allows tumor growth. However, macrophages associated with tumors are cells that are addicted to the transcription process. Lurbinectedin acts specifically on the macrophages associated with tumors in two ways: firstly, by inhibiting the transcription of macrophages that leads to cell death and secondly, inhibiting the production of tumor growth factors. In this way, lurbinectedin normalizes the tumor microenvironment.

History

Lurbinectedin was approved for medical use in the United States in June 2020.[5][1][2][3][6]

Efficacy was demonstrated in the PM1183-B-005-14 trial (Study B-005; NCT02454972), a multicenter open-label, multi-cohort study enrolling 105 participants with metastatic SCLC who had disease progression on or after platinum-based chemotherapy.[3][6] Participants received lurbinectedin 3.2 mg/m2 by intravenous infusion every 21 days until disease progression or unacceptable toxicity.[3] The trial was conducted at 26 sites in the United States, Great Britain, Belgium, France, Italy, Spain and Czech Republic.[6]

The U.S. Food and Drug Administration (FDA) granted the application for lurbinectedin priority review and orphan drug designations and granted the approval of Zepzelca to Pharma Mar S.A.[3][13]

Research

Clinical Trials

Lurbinectedin can be used as monotherapy in the treatment of SCLC.  Lurbinectedin monotherapy demonstrated the following clinical results in relapsed extensive stage SCLC:

  • For sensitive disease (chemotherapy-free interval of ≥ 90 days) overall response rate (ORR) was 46.6% with 79.3% disease control rate and median overall survival (OS) being increased to 15.2 months.[14]
  • For resistant disease (chemotherapy-free interval of < 90 days) overall response rate (ORR) was 21.3% with 46.8% disease control rate and 5.1 months median overall survival (OS).[14]

Lurbinectedin is also being investigated in combination with doxorubicin as second-line therapy in a randomized Phase III trial.[medical citation needed] While overall survival in this trial is not yet known, response rates at second line were

  • 91.7% in sensitive disease with median progression-free survival of 5.8 months, and
  • 33.3% in resistant disease with median progression-free of 3.5 months.[15]

Lurbinectedin is available in the U.S. under Expanded Access Program (EAP).[15][16]

SYN

SYN

WO2011/147828

Ecteinascidins is a group of naturally occurring marine compounds and analogs thereof, which are well identified and structurally characterized, and are disclosed to have antibacterial and cytotoxic properties. See for example, European Patent 309.477; WO 03/66638; WO 03/08423; WO 01 /771 15; WO 03/014127; R. Sakai et al., 1992, Proc. Natl. Acad. Sci. USA 89, pages 1 1456- 1 1460; R. Menchaca et al., 2003, J. Org. Chem. 68(23), pages 8859-8866; and I. Manzanares et al., 2001 , Curr. Med. Chem. Anti-Cancer Agents, 1 , pages 257-276; and references therein. Examples of ecteinascidins are provided by ET-743, ET-729, ET-745, ET-759A, ET-759B, ET-759C, ET-770, ET-815, ET-731 , ET-745B, ET-722, ET-736, ET-738, ET-808, ET-752, ET-594, ET-552, ET-637, ET-652, ET-583, ET-597, ET-596, ET-639, ET-641 , and derivatives thereof, such as acetylated forms, formylated forms, methylated forms, and oxide forms.

The structural characterizations of such ecteinascidins are not given again explicitly herein because from the detailed description provided in such references and citations any person of ordinary skill in this technology is capable of obtaining such information directly from the sources cited here and related sources.

At least one of the ecteinascidin compounds, ecteinascidin 743 (ET-743), has been extensively studied, and it will be referred to

specifically herein to illustrate features of this invention. ET-743 is being employed as an anticancer medicament, under the international nonproprietary name (INN) trabectedin, for the treatment of patients with advanced and metastatic soft tissue sarcoma (STS), after failure of anthracyclines and ifosfamide, or who are unsuited to receive such agents, and for the treatment of relapsed platinum- sensitive ovarian cancer in combination with pegylated liposomal doxorubicin.

ET-743 has a complex tris(tetrahydroisoquinoline) structure of formula

It was originally prepared by isolation from extracts of the marine tunicate Ecteinascidia turbinata. The yield was low, and alternative preparative processes had been sought.

The first synthetic process for producing ecteinascidin compounds was described in US Patent 5,721 ,362. This process employed sesamol as starting material and yielded ET-743 after a long and complicated sequence of 38 examples each describing one or more steps in the synthetic sequence.

An improvement in the preparation of one intermediate used in such process was disclosed in US Patent 6,815,544. Even with this improvement, the total synthesis was not suitable for manufacturing ET-743 at an industrial scale.

A hemisynthetic process for producing ecteinascidin compounds was described in EP 1.185.536. This process employs cyanosafracin B as starting material to provide ET-743. Cyanosafracin B is a pentacyclic antibiotic obtained by fermentation from the bacteria Pseudomonas fluorescens.

Cyanosafracin B

An improvement in such hemisynthetic process was disclosed in

EP 1.287.004.

To date four additional synthetic process (2 total and 2 formal synthesis) have been disclosed in patent applications JP 2003221395, WO 2007/045686, and WO 2007/087220 and in J. Org. Chem. 2008, 73, pages 9594-9600.

WO 2007/045686 also relates to the synthesis of Ecteinascidins-583 and 597 using intermediate compounds of formula:

Total synthesis strategies for the synthesis of the pentacyclic core -743 are overviewed in Figure I.

X = OH or CI

R = Protecting Group

WO2007087220 JOC 2008, 73, 9594-9600

EXAMPLE 3: SYNTHESIS OF COMPOUND 17.

Scheme X above provides an example of the synthesis of compound 17 from intermediate 10.

Compounds 16 and 17 are obtainable from intermediate 15 using the same procedures than those previously described in WO03/014127.

SYN

Reference:

1. WO2003014127A1.

https://patents.google.com/patent/WO2003014127A1/en

The ecteinascidins are exceedingly potent antitumour agents isolated from the marine tunicate Ecteinascidia turbinata. Several ecteinascidins have been reported previously in the patent and scientific literature. See, for example:

U.S. Patent No 5.256.663, which describes pharmaceutical compositions comprising matter extracted from the tropical marine invertebrate, Ecteinascidia turbinata, and designated therein as ecteinascidins, and the use of such compositions as antibacterial, antiviral, and/ or antitumour agents in mammals.

U.S. Patent No 5.089.273, which describes novel compositions of matter extracted from the tropical marine invertebrate, Ecteinascidia turbinata, and designated therein as ecteinascidins 729, 743, 745, 759A, 759B and 770. These compounds are useful as antibacterial and/or antitumour agents in mammals.

U.S. Patent No 5.149.804 which describes Ecteinascidins 722 and 736 (Et’s 722 and 736) isolated from the Caribbean tunicate Ecteinascidia turbinata and their structures. Et’s 722 and 736 protect mice in vivo at very low concentrations against P388 lymphoma, B 16 melanoma, and Lewis lung carcinoma.

U.S. Patent No 5.478.932, which describes ecteinascidins isolated from the Caribbean tunicate Ecteinascidia turbinata, which provide in vivo protection against P388 lymphoma, B 16 melanoma, M5076 ovarian sarcoma, Lewis lung carcinoma, and the LX- 1 human lung and MX- 1 human mammary carcinoma xenografts.

U.S. Patent No 5.654.426, which describes several ecteinascidins isolated from the Caribbean tunicate Ecteinascidia turbinata, which provide in vivo protection against P388 lymphoma, B 16 melanoma, M5076 ovarian sarcoma, Lewis lung carcinoma, and the LX-1 human lung and MX- 1 human mammary carcinoma xenografts.

U.S. Patent No 5.721.362 which describes a synthetic process for the formation of ecteinascidin compounds and related structures.

U.S. Patent No 6.124.292 which describes a series of new ecteinascidin- like compounds.

WO 0177115, WO 0187894 and WO 0187895, which describe new synthetic compounds of the ecteinascidin series, their synthesis and biological properties.

See also: Corey, E.J., J. Am. Chem. Soc, 1996, 118 pp. 9202-9203; Rinehart, et al., Journal of Natural Products, 1990, “Bioactive Compounds from Aquatic and Terrestrial Sources”, vol. 53, pp. 771- 792; Rinehart et al., Pure and Appl. Chem., 1990, “Biologically active natural products”, vol 62, pp. 1277- 1280; Rinehart, et al., J. Org. Chem., 1990, “Ecteinascidins 729, 743, 745, 759A, 759B, and 770: potent Antitumour Agents from the Caribbean Tunicate Ecteinascidia tuminata”, vol. 55, pp. 4512-4515; Wright et al., J. Org. Chem., 1990, “Antitumour Tetrahydroisoquinoline Alkaloids from the Colonial ascidian Ecteinascidia turbinata”, vol. 55, pp. 4508-4512; Sakai et al., Proc. Natl. Acad. Sci. USA 1992, “Additional anitumor ecteinascidins from a Caribbean tunicate: Crystal structures and activities in vivo”, vol. 89, 1 1456- 1 1460; Science 1994, “Chemical Prospectors Scour the Seas for Promising Drugs”, vol. 266, pp.1324; Koenig, K.E., “Asymmetric Synthesis”, ed. Morrison, Academic Press, Inc., Orlando, FL, vol. 5, 1985, p. 71; Barton, et al., J. Chem Soc. Perkin Trans., 1 , 1982, “Synthesis and Properties of a Series of Sterically Hindered Guanidine bases”, pp. 2085; Fukuyama et al., J. Am. Chem. Soc, 1982, “Stereocontrolled Total Synthesis of (+)-Saframycin B”, vol. 104, pp. 4957; Fukuyama et al., J. Am. Chem. Soc, 1990, “Total Synthesis of (+) – Saframycin A”, vol. 112, p. 3712; Saito, et al., J. Org. Chem., 1989, “Synthesis of Saframycins. Preparation of a Key tricyclic Lactam Intermediate to Saframycin A”, vol. 54, 5391; Still, et al., J Org. Chem., 1978, “Rapid Chromatographic Technique for Preparative Separations with Moderate Resolution”, vol. 43, p. 2923; Kofron, W.G.; Baclawski, L.M., J. Org. Chem., 1976, vol. 41, 1879; Guan et al., J. Biomolec Struc & Dynam., vol. 10, pp. 793-817 (1993); Shamma et al., “Carbon- 13 NMR Shift Assignments of Amines and Alkaloids”, p. 206 (1979); Lown et al., Biochemistry, 21, 419-428 (1982); Zmijewski et al., Chem. Biol. Interactions, 52, 361-375 (1985); Ito, CRC Crit. Rev. Anal. Chem., 17, 65- 143 (1986); Rinehart et al., “Topics in Pharmaceutical Sciences 1989”, pp. 613-626, D. D. Breimer, D. J. A. Cromwelin, K. K. Midha, Eds., Amsterdam Medical Press B. V., Noordwijk, The Netherlands (1989); Rinehart et al., “Biological Mass Spectrometry”, 233-258 eds. Burlingame et al., Elsevier Amsterdam (1990); Guan et al., Jour. Biomolec. Struct. & Dynam., vol. 10 pp. 793-817 (1993); Nakagawa et al., J. Amer. Chem. Soc, 11 1 : 2721-2722 (1989);; Lichter et al., “Food and Drugs from the Sea Proceedings” (1972), Marine Technology Society, Washington, D.C. 1973, 117- 127; Sakai et al., J. Amer. Chem. Soc, 1996, 1 18, 9017; Garcϊa-Rocha et al., Brit. J. Cancer, 1996, 73: 875-883; and pommier et al., Biochemistry, 1996, 35: 13303- 13309;

In 2000, a hemisynthetic process for the formation of ecteinascidin compounds and related structures such as phthalascidin starting from natural bis(tetrahydroisoquinoline) alkaloids such as the saframycin and safracin antibiotics available from different culture broths was reported; See Manzanares et al., Org. Lett., 2000, “Synthesis of Ecteinascidin ET-743 and Phthalascidin Pt-650 from Cyanosafracin B”, Vol. 2, No 16, pp. 2545-2548; and International Patent Application WO 00 69862.

Ecteinascidin 736 was first discovered by Rinehart and features a tetrahydro-β-carboline unit in place of the tetrahydroisoquinoline unit more usually found in the ecteinascidin compounds isolated from natural sources; See for example Sakai et al., Proc. Natl. Acad. Sci. USA 1992, “Additional antitumor ecteinascidins from a Caribbean tunicate: Crystal structures and activities in vivo”, vol. 89, 11456-11460.

Figure imgf000005_0001

Et-736

WO 9209607 claims ecteinascidin 736, as well as ecteinascidin 722 with hydrogen in place of methyl on the nitrogen common to rings C and D of ecteinascidin 736 and O-methylecteinascidin 736 with methoxy in place of hydroxy on ring C of ecteinascidin 736.

Despite the positive results obtained in clinical applications in chemotherapy, the search in the field of ecteinascidin compounds is still open to the identification of new compounds with optimal features of cytotoxicity and selectivity toward the tumour and with a reduced systemic toxicity and improved pharmacokinetic properties.

PATENT

WO2001087894A1.

PATENT

 US 20130066067

https://patents.google.com/patent/US20130066067A1/en

  • Ecteinascidins is a group of naturally occurring marine compounds and analogs thereof, which are well identified and structurally characterized, and are disclosed to have antibacterial and cytotoxic properties. See for example, European Patent 309.477; WO 03/66638; WO 03/08423; WO 01/77115; WO 03/014127; R. Sakai et al., 1992, Proc. Natl. Acad. Sci. USA 89, pages 11456-11460; R. Menchaca et al., 2003, J. Org. Chem. 68(23), pages 8859-8866; and I. Manzanares et al., 2001, Curr. Med. Chem. AntiCancer Agents, 1, pages 257-276; and references therein. Examples of ecteinascidins are provided by ET-743, ET-729, ET-745, ET-759A, ET-759B, ET-759C, ET-770, ET-815, ET-731, ET-745B, ET-722, ET-736, ET-738, ET-808, ET-752, ET-594, ET-552, ET-637, ET-652, ET-583, ET-597, ET-596, ET-639, ET-641, and derivatives thereof, such as acetylated forms, formylated forms, methylated forms, and oxide forms.
  • [0003]
    The structural characterizations of such ecteinascidins are not given again explicitly herein because from the detailed description provided in such references and citations any person of ordinary skill in this technology is capable of obtaining such information directly from the sources cited here and related sources.
  • [0004]
    At least one of the ecteinascidin compounds, ecteinascidin 743 (ET-743), has been extensively studied, and it will be referred to specifically herein to illustrate features of this invention. ET-743 is being employed as an anticancer medicament, under the international nonproprietary name (INN) trabectedin, for the treatment of patients with advanced and metastatic soft tissue sarcoma (STS), after failure of anthracyclines and ifosfamide, or who are unsuited to receive such agents, and for the treatment of relapsed platinum-sensitive ovarian cancer in combination with pegylated liposomal doxorubicin.
  • [0005]
    ET-743 has a complex tris(tetrahydroisoquinoline) structure of formula
  • [0006]
    It was originally prepared by isolation from extracts of the marine tunicate Ecteinascidia turbinata. The yield was low, and alternative preparative processes had been sought.
  • [0007]
    The first synthetic process for producing ecteinascidin compounds was described in U.S. Pat. No. 5,721,362. This process employed sesamol as starting material and yielded ET-743 after a long and complicated sequence of 38 examples each describing one or more steps in the synthetic sequence.
  • [0008]
    An improvement in the preparation of one intermediate used in such process was disclosed in U.S. Pat. No. 6,815,544. Even with this improvement, the total synthesis was not suitable for manufacturing ET-743 at an industrial scale.
  • [0009]
    A hemisynthetic process for producing ecteinascidin compounds was described in EP 1.185.536. This process employs cyanosafracin B as starting material to provide ET-743. Cyanosafracin B is a pentacyclic antibiotic obtained by fermentation from the bacteria Pseudomonas fluorescens.
  • [0010]
    An improvement in such hemisynthetic process was disclosed in EP 1.287.004.
  • [0011]
    To date four additional synthetic process (2 total and 2 formal synthesis) have been disclosed in patent applications JP 2003221395, WO 2007/045686, and WO 2007/087220 and in J. Org. Chem. 2008, 73, pages 9594-9600.
  • [0012]
    WO 2007/045686 also relates to the synthesis of Ecteinascidins-583 and 597 using intermediate compounds of formula:
  • [0013]
    Total synthesis strategies for the synthesis of the pentacyclic core of ET-743 are overviewed in FIG. 1.

PAPER

Angewandte Chemie, International Edition (2019), 58(12), 3972-3975.

https://onlinelibrary.wiley.com/doi/abs/10.1002/anie.201900035

An efficient and scalable approach is described for the total synthesis of the marine natural product Et‐743 and its derivative lubinectedin, which are valuable antitumor compounds. The method delivers 1.6 % overall yield in 26 total steps from Cbz‐protected (S)‐tyrosine. It features the use of a common advanced intermediate to create the right and left parts of these compounds, and a light‐mediated remote C−H bond activation to assemble a benzo[1,3]dioxole‐containing intermediate.

Synthesis of lactone SI-5. A mixture of 19 (98.0 mg, 0.16 mmol, 1.0 equiv), 2-(5-methoxy-1H-indol-3-yl) ethanamine hydrochloride salt (357.8 mg, 1.58 mmol, 10.0 equiv) and NaOAc (144 mg, 1.74 mmol, 11.0 equiv) in anhydrous EtOH (5.0 mL) was stirred at 60 oC for 5 h. The cooled mixture was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (eluting with DCM/MeOH = 20:1) to afford compound SI-5 (109 mg, 87%). [α]𝐷 20 = -27.7 (c = 1.0, CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.61 (s, 1H), 7.13 (d, J = 8.8 Hz, 1H), 6.82 (d, J = 2.2 Hz, 1H), 6.75 (dd, J = 8.8, 2.4 Hz, 1H), 6.66 (s, 1H), 6.22 (d, J = 1.0 Hz, 1H), 6.02 (d, J = 1.0 Hz, 1H), 5.78 (s, 1H), 5.08 (d, J = 11.7 Hz, 1H), 4.55 (s, 1H), 4.32 (s, 1H), 4.27 (d, J = 3.8 Hz, 1H), 4.23–4.15 (m, 2H), 3.81 (s, 3H), 3.79 (s, 3H), 3.47–3.39 (m, 2H), 3.20–3.10 (m, 1H), 3.06 (d, J = 18.1 Hz, 1H), 2.93 (dd, J = 18.2, 9.1 Hz, 1H), 2.86–2.76 (m, 1H), 2.62 (dt, J = 14.9, 4.8 Hz, 1H), 2.56–2.47 (m, 2H), 2.37 (s, 3H), 2.30–2.27 (m, 1H), 2.26 (s, 3H), 2.22 (s, 3H), 2.06 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 171.6, 168.8, 154.0, 148.2, 145.8, 143.1, 141.3, 140.5, 131.4, 130.8, 130.7, 129.4, 127.3, 120.9, 120.8, 118.4, 118.4, 113.9, 113.8, 112.2, 111.8, 110.2, 102.2, 100.5, 62.6, 61.4, 60.7, 60.5, 59.6, 59.6, 55.9, 54.9, 54.8, 42.1, 41.6, 39.9, 39.5, 29.5, 24.0, 20.8, 16.0, 9.9; HRMS (ESI) m/z calcd. for C42H43N5O9S [M + H]+ 794.2860, found 794.2858

Lurbinectedin: To a solution of SI-5 (80 mg, 0.1 mmol, 1.0 equiv) in acetonitrile and water (3:2, v/v, 10 mL) was added silver nitrate (514 mg, 3 mmol, 30.0 equiv). The suspension was stirred at 25 oC for 24 h before a mixture of saturated brine (5.0 mL) and saturated sodium hydrogen carbonate (5 mL) were added. The resultant mixture was stirred at 25 oC for 15 min before it was filtered through celite and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over sodium sulfate and concentrated, and the residue was purified by flash column chromatography (eluting with DCM/MeOH = 20:1) to afford Lurbinectedin (71 mg, 89%). [α]𝐷 20 = -45.0 (c = 1.0, CHCl3) 1H NMR (400 MHz, CDCl3) δ 7.61 (s, 1H), 7.13 (d, J = 8.8 Hz, 1H), 6.82 (d, J = 2.2 Hz, 1H), 6.74 (dd, J = 8.8, 2.4 Hz, 1H), 6.67 (s, 1H), 6.19 (d, J = 1.1 Hz, 1H), 5.99 (d, J = 1.1 Hz, 1H), 5.77 (br s, 1H), 5.20 (d, J = 11.3 Hz, 1H), 4.82 (s, 1H), 4.53–4.40 (m, 2H), 4.18–4.08 (m, 2H), 3.81 (s, 3H), 3.79 (s, 3H), 3.49 (d, J = 4.2 Hz, 1H), 3.24–3.13 (m, 2H), 3.01 (d, J = 17.9 Hz, 1H), 2.88–2.79 (m, 2H), 2.63 (dt, J = 15.0, 4.9 Hz, 1H), 2.56–2.47 (m, 2H), 2.37 (s, 3H), 2.32–2.27 (m, 1H), 2.26 (s, 3H), 2.19 (s, 3H), 2.05 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 171.4, 168.8, 153.8, 147.9, 145.5, 142.9, 141.1, 140.7, 131.8, 131.3, 130.7, 129.1, 127.3, 121.4, 121.0, 118.2, 115.6, 112.9, 111.9, 111.7, 110.0, 101.8, 100.4, 82.0, 62.4, 61.9, 60.4, 57.8, 57.5, 56.0, 55.8, 55.0, 42.2, 41.3, 39.8, 39.3, 29.3, 23.6, 20.6, 15.9, 9.7; HRMS (ESI) m/z calcd. for C41H44N4O10S [M – OH]+ 767.2745, found 767.2742.

References

  1. Jump up to:a b c d e “Zepzelca- lurbinectedin injection, powder, lyophilized, for solution”DailyMed. 15 June 2020. Retrieved 24 September 2020.
  2. Jump up to:a b c d “Jazz Pharmaceuticals Announces U.S. FDA Accelerated Approval of Zepzelca (lurbinectedin) for the Treatment of Metastatic Small Cell Lung Cancer” (Press release). Jazz Pharmaceuticals. 15 June 2020. Retrieved 15 June 2020 – via PR Newswire.
  3. Jump up to:a b c d e f g “FDA grants accelerated approval to lurbinectedin for metastatic small”U.S. Food and Drug Administration (FDA). 15 June 2020. Retrieved 16 June 2020.  This article incorporates text from this source, which is in the public domain.
  4. Jump up to:a b “Lurbinectedin”National Cancer Institute. Retrieved 15 June 2020.  This article incorporates text from this source, which is in the public domain.
  5. Jump up to:a b “Zepzelca: FDA-Approved Drugs”U.S. Food and Drug Administration (FDA). Retrieved 15 June 2020.
  6. Jump up to:a b c d “Drug Trials Snapshots: Zepzelca”U.S. Food and Drug Administration (FDA). 15 June 2020. Retrieved 28 June 2020.  This article incorporates text from this source, which is in the public domain.
  7. ^ Takahashi, Ryoko; Mabuchi, Seiji; Kawano, Mahiru; Sasano, Tomoyuki; Matsumoto, Yuri; Kuroda, Hiromasa; Kozasa, Katsumi; Hashimoto, Kae; Sawada, Kenjiro; Kimura, Tadashi (17 March 2016). “Preclinical Investigations of PM01183 (Lurbinectedin) as a Single Agent or in Combination with Other Anticancer Agents for Clear Cell Carcinoma of the Ovary”PLOS ONE11 (3): e0151050. Bibcode:2016PLoSO..1151050Tdoi:10.1371/journal.pone.0151050PMC 4795692PMID 26986199.
  8. ^ Total synthesis of marine antitumor agents trabectedin and lurbinectedin | https://www.sciencedaily.com/releases/2019/02/190219111659.htm
  9. ^ A Scalable Total Synthesis of the Antitumor Agents Et‐743 and Lurbinectedin | https://onlinelibrary.wiley.com/doi/full/10.1002/anie.201900035
  10. ^ PharmaMar presentation of Lurbinectedin’s Mechanism of Action Lurbinectedin Mechanisim of Action | https://www.youtube.com/watch?v=8daELhxAXcQ
  11. ^ Qian BZ, Pollard JW (April 2010). “Macrophage diversity enhances tumor progression and metastasis”Cell141 (1): 39–51. doi:10.1016/j.cell.2010.03.014PMC 4994190PMID 20371344.
  12. ^ Engblom C, Pfirschke C, Pittet MJ (July 2016). “The role of myeloid cells in cancer therapies”. Nature Reviews. Cancer16 (7): 447–62. doi:10.1038/nrc.2016.54PMID 27339708S2CID 21924175.
  13. ^ “Lurbinectedin Orphan Drug Designation and Approval”U.S. Food and Drug Administration (FDA). 1 August 2018. Retrieved 16 June 2020.
  14. Jump up to:a b Paz-Ares, Luis G.; Trigo Perez, Jose Manuel; Besse, Benjamin; Moreno, Victor; Lopez, Rafael; Sala, Maria Angeles; Ponce Aix, Santiago; Fernandez, Cristian Marcelo; Siguero, Mariano; Kahatt, Carmen Maria; Zeaiter, Ali Hassan; Zaman, Khalil; Boni, Valentina; Arrondeau, Jennifer; Martinez Aguillo, Maite; Delord, Jean-Pierre; Awada, Ahmad; Kristeleit, Rebecca Sophie; Olmedo Garcia, Maria Eugenia; Subbiah, Vivek (20 May 2019). “Efficacy and safety profile of lurbinectedin in second-line SCLC patients: Results from a phase II single-agent trial”. Journal of Clinical Oncology37 (15_suppl): 8506. doi:10.1200/JCO.2019.37.15_suppl.8506.
  15. Jump up to:a b Calvo, E.; Moreno, V.; Flynn, M.; Holgado, E.; Olmedo, M.E.; Lopez Criado, M.P.; Kahatt, C.; Lopez-Vilariño, J.A.; Siguero, M.; Fernandez-Teruel, C.; Cullell-Young, M.; Soto Matos-Pita, A.; Forster, M. (October 2017). “Antitumor activity of lurbinectedin (PM01183) and doxorubicin in relapsed small-cell lung cancer: results from a phase I study”Annals of Oncology28 (10): 2559–2566. doi:10.1093/annonc/mdx357PMC 5834091PMID 28961837Lay summary.
  16. ^ Farago, Anna F; Drapkin, Benjamin J; Lopez-Vilarino de Ramos, Jose Antonio; Galmarini, Carlos M; Núñez, Rafael; Kahatt, Carmen; Paz-Ares, Luis (January 2019). “ATLANTIS: a Phase III study of lurbinectedin/doxorubicin versus topotecan or cyclophosphamide/doxorubicin/vincristine in patients with small-cell lung cancer who have failed one prior platinum-containing line”Future Oncology15 (3): 231–239. doi:10.2217/fon-2018-0597PMC 6331752PMID 30362375.

External links

FDA grants accelerated approval to lurbinectedin for metastatic small cell lung cancer

On June 15, 2020, the Food and Drug Administration granted accelerated approval to lurbinectedin(ZEPZELCA, Pharma Mar S.A.) for adult patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy.

Efficacy was demonstrated in the PM1183-B-005-14 trial (Study B-005; NCT02454972), a multicenter open-label, multi-cohort study enrolling 105 patients with metastatic SCLC who had disease progression on or after platinum-based chemotherapy. Patients received lurbinectedin 3.2 mg/m2 by intravenous infusion every 21 days until disease progression or unacceptable toxicity.

The main efficacy outcome measures were confirmed overall response rate (ORR) determined by investigator assessment using RECIST 1.1 and response duration. Among the 105 patients, the ORR was 35% (95% CI: 26%, 45%), with a median response duration of 5.3 months (95% CI: 4.1, 6.4). The ORR as per independent review committee was 30% (95% CI: 22%, 40%) with a median response duration of 5.1 months (95% CI: 4.9, 6.4).

The most common adverse reactions (≥20%), including laboratory abnormalities, were myelosuppression, fatigue, increased creatinine, increased alanine aminotransferase, increased glucose, nausea, decreased appetite, musculoskeletal pain, decreased albumin, constipation, dyspnea, decreased sodium, increased aspartate aminotransferase, vomiting, cough, decreased magnesium and diarrhea.

The recommended lurbinectedin dose is 3.2 mg/m2 every 21 days.

View full prescribing information for ZEPZELCA.

This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this application, a modified Project Orbis was undertaken because of the timing of submission to other regulatory agencies. FDA is collaborating with the Australian Therapeutic Goods Administration (TGA). FDA approved this application 2 months ahead of the goal date. The review is ongoing for the Australian TGA.

FDA granted lurbinectedin orphan drug  designation for the treatment of SCLC and priority review to this application. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

REFERENCES

1: Calvo E, Moreno V, Flynn M, Holgado E, Olmedo ME, Lopez Criado MP, Kahatt C, Lopez-Vilariño JA, Siguero M, Fernandez-Teruel C, Cullell-Young M, Soto Matos-Pita A, Forster M. Antitumor activity of lurbinectedin (PM01183) and doxorubicin in relapsed small-cell lung cancer: results from a phase I study. Ann Oncol. 2017 Oct 1;28(10):2559-2566. doi: 10.1093/annonc/mdx357. PubMed PMID: 28961837.

2: Erba E, Romano M, Gobbi M, Zucchetti M, Ferrari M, Matteo C, Panini N, Colmegna B, Caratti G, Porcu L, Fruscio R, Perlangeli MV, Mezzanzanica D, Lorusso D, Raspagliesi F, D’Incalci M. Ascites interferes with the activity of lurbinectedin and trabectedin: Potential role of their binding to alpha 1-acid glycoprotein. Biochem Pharmacol. 2017 Nov 15;144:52-62. doi: 10.1016/j.bcp.2017.08.001. Epub 2017 Aug 4. PubMed PMID: 28782526.

3: Belgiovine C, Bello E, Liguori M, Craparotta I, Mannarino L, Paracchini L, Beltrame L, Marchini S, Galmarini CM, Mantovani A, Frapolli R, Allavena P, D’Incalci M. Lurbinectedin reduces tumour-associated macrophages and the inflammatory tumour microenvironment in preclinical models. Br J Cancer. 2017 Aug 22;117(5):628-638. doi: 10.1038/bjc.2017.205. Epub 2017 Jul 6. PubMed PMID: 28683469; PubMed Central PMCID: PMC5572168.

4: Jimeno A, Sharma MR, Szyldergemajn S, Gore L, Geary D, Diamond JR, Fernandez Teruel C, Soto Matos-Pita A, Iglesias JL, Cullell-Young M, Ratain MJ. Phase I study of lurbinectedin, a synthetic tetrahydroisoquinoline that inhibits activated transcription, induces DNA single- and double-strand breaks, on a weekly × 2 every-3-week schedule. Invest New Drugs. 2017 Aug;35(4):471-477. doi: 10.1007/s10637-017-0427-2. Epub 2017 Jan 20. PubMed PMID: 28105566.

5: Paz-Ares L, Forster M, Boni V, Szyldergemajn S, Corral J, Turnbull S, Cubillo A, Teruel CF, Calderero IL, Siguero M, Bohan P, Calvo E. Phase I clinical and pharmacokinetic study of PM01183 (a tetrahydroisoquinoline, Lurbinectedin) in combination with gemcitabine in patients with advanced solid tumors. Invest New Drugs. 2017 Apr;35(2):198-206. doi: 10.1007/s10637-016-0410-3. Epub 2016 Nov 21. PubMed PMID: 27873130.

6: Harlow ML, Maloney N, Roland J, Guillen Navarro MJ, Easton MK, Kitchen-Goosen SM, Boguslawski EA, Madaj ZB, Johnson BK, Bowman MJ, D’Incalci M, Winn ME, Turner L, Hostetter G, Galmarini CM, Aviles PM, Grohar PJ. Lurbinectedin Inactivates the Ewing Sarcoma Oncoprotein EWS-FLI1 by Redistributing It within the Nucleus. Cancer Res. 2016 Nov 15;76(22):6657-6668. doi: 10.1158/0008-5472.CAN-16-0568. Epub 2016 Oct 3. PubMed PMID: 27697767; PubMed Central PMCID: PMC5567825.

7: Céspedes MV, Guillén MJ, López-Casas PP, Sarno F, Gallardo A, Álamo P, Cuevas C, Hidalgo M, Galmarini CM, Allavena P, Avilés P, Mangues R. Lurbinectedin induces depletion of tumor-associated macrophages, an essential component of its in vivo synergism with gemcitabine, in pancreatic adenocarcinoma mouse models. Dis Model Mech. 2016 Dec 1;9(12):1461-1471. Epub 2016 Oct 20. PubMed PMID: 27780828; PubMed Central PMCID: PMC5200894.

8: Santamaría Nuñez G, Robles CM, Giraudon C, Martínez-Leal JF, Compe E, Coin F, Aviles P, Galmarini CM, Egly JM. Lurbinectedin Specifically Triggers the Degradation of Phosphorylated RNA Polymerase II and the Formation of DNA Breaks in Cancer Cells. Mol Cancer Ther. 2016 Oct;15(10):2399-2412. Epub 2016 Sep 14. PubMed PMID: 27630271.

9: Metaxas Y, Cathomas R, Mark M, von Moos R. Combination of cisplatin and lurbinectedin as palliative chemotherapy in progressive malignant pleural mesothelioma: Report of two cases. Lung Cancer. 2016 Dec;102:136-138. doi: 10.1016/j.lungcan.2016.07.012. Epub 2016 Jul 14. PubMed PMID: 27440191.

10: Lima M, Bouzid H, Soares DG, Selle F, Morel C, Galmarini CM, Henriques JA, Larsen AK, Escargueil AE. Dual inhibition of ATR and ATM potentiates the activity of trabectedin and lurbinectedin by perturbing the DNA damage response and homologous recombination repair. Oncotarget. 2016 May 3;7(18):25885-901. doi: 10.18632/oncotarget.8292. PubMed PMID: 27029031; PubMed Central PMCID: PMC5041952.

11: Takahashi R, Mabuchi S, Kawano M, Sasano T, Matsumoto Y, Kuroda H, Kozasa K, Hashimoto K, Sawada K, Kimura T. Preclinical Investigations of PM01183 (Lurbinectedin) as a Single Agent or in Combination with Other Anticancer Agents for Clear Cell Carcinoma of the Ovary. PLoS One. 2016 Mar 17;11(3):e0151050. doi: 10.1371/journal.pone.0151050. eCollection 2016. PubMed PMID: 26986199; PubMed Central PMCID: PMC4795692.

12: Pernice T, Bishop AG, Guillen MJ, Cuevas C, Aviles P. Development of a liquid chromatography/tandem mass spectrometry assay for the quantification of PM01183 (lurbinectedin), a novel antineoplastic agent, in mouse, rat, dog, Cynomolgus monkey and mini-pig plasma. J Pharm Biomed Anal. 2016 May 10;123:37-41. doi: 10.1016/j.jpba.2016.01.043. Epub 2016 Jan 21. PubMed PMID: 26871278.

13: Elez ME, Tabernero J, Geary D, Macarulla T, Kang SP, Kahatt C, Pita AS, Teruel CF, Siguero M, Cullell-Young M, Szyldergemajn S, Ratain MJ. First-in-human phase I study of Lurbinectedin (PM01183) in patients with advanced solid tumors. Clin Cancer Res. 2014 Apr 15;20(8):2205-14. doi: 10.1158/1078-0432.CCR-13-1880. Epub 2014 Feb 21. PubMed PMID: 24563480.

14: Romano M, Frapolli R, Zangarini M, Bello E, Porcu L, Galmarini CM, García-Fernández LF, Cuevas C, Allavena P, Erba E, D’Incalci M. Comparison of in vitro and in vivo biological effects of trabectedin, lurbinectedin (PM01183) and Zalypsis® (PM00104). Int J Cancer. 2013 Nov;133(9):2024-33. doi: 10.1002/ijc.28213. Epub 2013 May 25. PubMed PMID: 23588839.

15: Vidal A, Muñoz C, Guillén MJ, Moretó J, Puertas S, Martínez-Iniesta M, Figueras A, Padullés L, García-Rodriguez FJ, Berdiel-Acer M, Pujana MA, Salazar R, Gil-Martin M, Martí L, Ponce J, Molleví DG, Capella G, Condom E, Viñals F, Huertas D, Cuevas C, Esteller M, Avilés P, Villanueva A. Lurbinectedin (PM01183), a new DNA minor groove binder, inhibits growth of orthotopic primary graft of cisplatin-resistant epithelial ovarian cancer. Clin Cancer Res. 2012 Oct 1;18(19):5399-411. doi: 10.1158/1078-0432.CCR-12-1513. Epub 2012 Aug 15. PubMed PMID: 22896654.

Clinical data
PronunciationLOOR-bih-NEK-teh-din
Trade namesZepzelca
Other namesPM-01183
AHFS/Drugs.comProfessional Drug Facts
MedlinePlusa620049
License dataUS DailyMedLurbinectedin
Pregnancy
category
US: N (Not classified yet)
Routes of
administration
Intravenous
Drug classAntineoplastic agent
ATC codeNone
Legal status
Legal statusUS: ℞-only [1]
Identifiers
IUPAC name[show]
CAS Number497871-47-3
PubChem CID57327016
DrugBank12674
ChemSpider32701856
UNII2CN60TN6ZS
KEGGD11644
ChEMBLChEMBL4297516
CompTox Dashboard (EPA)DTXSID30198065 
Chemical and physical data
FormulaC41H44N4O10S
Molar mass784.88 g·mol−1
3D model (JSmol)Interactive image
SMILES[hide]CC1=CC2=C([C@@H]3[C@@H]4[C@H]5C6=C(C(=C7C(=C6[C@@H](N4[C@H]([C@H](C2)N3C)O)COC(=O)[C@@]8(CS5)C9=C(CCN8)C2=C(N9)C=CC(=C2)OC)OCO7)C)OC(=O)C)C(=C1OC)O
InChI[hide]InChI=1S/C41H44N4O10S/c1-17-11-20-12-25-39(48)45-26-14-52-40(49)41(38-22(9-10-42-41)23-13-21(50-5)7-8-24(23)43-38)15-56-37(31(45)30(44(25)4)27(20)32(47)33(17)51-6)29-28(26)36-35(53-16-54-36)18(2)34(29)55-19(3)46/h7-8,11,13,25-26,30-31,37,39,42-43,47-48H,9-10,12,14-16H2,1-6H3/t25-,26-,30+,31+,37+,39-,41+/m0/s1Key:YDDMIZRDDREKEP-HWTBNCOESA-N

//////////lurbinectedin,  FDA 2020, 2020 APPROVALS, ORPHAN, priority review , ZEPZELCA, Pharma Mar, PM-1183, PM 1183, PM 01183, лурбинектедин , لوربينيكتيدين  , 芦比替定

Cc1cc2c(c(c1OC)O)[C@@H]3[C@@H]4[C@H]5c6c(c7c(c(c6OC(=O)C)C)OCO7)[C@@H](N4[C@H]([C@H](C2)N3C)O)COC(=O)[C@@]8(CS5)c9c(c1cc(ccc1[nH]9)OC)CCN8

LENALIDOMIDE, レナリドミド, леналидомид , ليناليدوميد , 来那度胺 ,


Lenalidomide

ChemSpider 2D Image | Lenalidomide | C13H13N3O3

LENALIDOMIDE

  • Molecular FormulaC13H13N3O3
  • Average mass259.261 Da
レナリドミド;

леналидомид ليناليدوميد 来那度胺 

191732-72-6 [RN]
1-Oxo-4-amino-2-(2,6-dioxopiperidin-3-yl)isoindole
2,6-Piperidinedione, 3-(4-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-
3-(4-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-2,6-piperidinedione
3-(4-Amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-2,6-piperidinedione
3-(4-Amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidin-2,6-dion
3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione
3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione
3-(7-amino-3-oxo-1h-isoindol-2-yl)piperidine-2,6-dione
8505
E3 Ligase ligand
IMiD3
CAS Registry Number: 191732-72-6
CAS Name: 3-(4-Amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-2,6-piperidinedione
Additional Names: 1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline
Manufacturers’ Codes: CC-5013
Trademarks: Revimid (Celgene); Revlimid (Celgene)
Molecular Formula: C13H13N3O3
Molecular Weight: 259.26
Percent Composition: C 60.22%, H 5.05%, N 16.21%, O 18.51%
Literature References: Immunomodulatory drug; analog of thalidomide, q.v. Prepn: G. W. Muller et al., US 5635517 (1997 to Celgene); and in vitro TNF-a inhibition: eidem, Bioorg. Med. Chem. Lett. 9, 1625 (1999). LC-MS determn in plasma: T. M. Tohnya et al., J. Chromatogr. B 811, 135 (2004). Clinical evaluation in multiple myeloma: P. G. Richardson et al., Blood 100, 3063 (2002); in myelodysplastic syndromes: A. List et al., N. Engl. J. Med. 352, 549 (2005). Review of development, pharmacology and therapeutic potential: J. B. Bartlett et al., Nature Rev. 4, 314-322 (2004); C. S. Mitsiades, N. Mitsiades, Curr. Opin. Invest. Drugs 5, 635-647 (2004).
Therap-Cat: Immunomodulator.
Keywords: Immunomodulator.
  • 191732-72-6
  • SYP-1512
  • LENALIDOMIDE [VANDF]
  • LENALIDOMIDE [WHO-DD]
  • LENALIDOMIDE [EMA EPAR]
  • LENALIDOMIDE [MI]
  • LENALIDOMIDE [MART.]
  • LENALIDOMIDE [ORANGE BOOK]
  • LENALIDOMIDE [USAN]
  • LENALIDOMIDE [INN]
  • CDC-501
  • REVLIMID
  • LENALIDOMIDE
  • 3-(4-AMINO-1-OXO-1,3-DIHYDRO-2H-ISOINDOL-2-YL)PIPERIDINE-2,6-DIONE
  • 2,6-PIPERIDINEDIONE, 3-(4-AMINO-1,3-DIHYDRO-1-OXO-2H-ISOINDOL-2-YL)-
  • CC-5013

Lenalidomide (trade name Revlimid) is a derivative of thalidomide approved in the United States in 2005.[1]

It was initially intended as a treatment for multiple myeloma, for which thalidomide is an accepted therapeutic treatment. Lenalidomide has also shown efficacy in the class of hematological disorders known as myelodysplastic syndromes (MDS). Along with several other drugs developed in recent years, lenalidomide has significantly improved overall survival in myeloma (which formerly carried a poor prognosis), although toxicity remains an issue for users.[2] It costs $163,381 per year for the average patient.[3]

It is on the World Health Organization’s List of Essential Medicines, the safest and most effective medicines needed in a health system.[4]

Medical uses

Multiple myeloma

Multiple myeloma is a cancer of the blood, characterized by accumulation of a plasma cell clone in the bone marrow.[5] Lenalidomide is one of the novel drug agents used to treat multiple myeloma. It is a more potent molecular analog of thalidomide, which inhibits tumor angiogenesis, tumor secreted cytokines and tumor proliferation through the induction of apoptosis.[6][7][8]

Compared to placebo, lenalidomide is effective at inducing a complete or “very good partial” response as well as improving progression-free survival. Adverse events more common in people receiving lenalidomide for myeloma were neutropenia (a decrease in the white blood cell count), deep vein thrombosisinfections, and an increased risk of other hematological malignancies.[9] The risk of second primary hematological malignancies does not outweigh the benefit of using lenalidomide in relapsed or refractory multiple myeloma.[10] It may be more difficult to mobilize stem cells for autograft in people who have received lenalidomide.[6]

On 29 June 2006, lenalidomide received U.S. Food and Drug Administration (FDA) clearance for use in combination with dexamethasone in patients with multiple myeloma who have received at least one prior therapy.[11] On 22 February 2017, the FDA approved lenalidomide as standalone maintenance therapy (without dexamethasone) for patients with multiple myeloma following autologous stem cell transplant.[12]

On 23 April 2009, The National Institute for Health and Clinical Excellence (NICE) issued a Final Appraisal Determination (FAD) approving lenalidomide, in combination with dexamethasone, as an option to treat patients with multiple myeloma who have received two or more prior therapies in England and Wales.[13]

On 5 June 2013, the FDA designated lenalidomide as a specialty drug requiring a specialty pharmacy distribution for “use in mantle cell lymphoma (MCL) in patients whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib.” Revlimid is only available through a specialty pharmacy, “a restricted distribution program in conjunction with a risk evaluation and mitigation strategy (REMS) due to potential for embryo-fetal risk.”[14]

Myelodysplastic syndromes

With myelodysplastic syndromes (MDS), the best results of lenalidomide were obtained in patients with the Chromosome 5q deletion syndrome (5q- syndrome).[15] The syndrome results from deletions in human chromosome 5 that remove three adjacent genes, granulocyte-macrophage colony-stimulating factorPlatelet-derived growth factor receptor B, and Colony stimulating factor 1 receptor.[16][17]

It was approved by the FDA on 27 December 2005, for patients with low or intermediate-1 risk MDS with 5q- with or without additional cytogenetic abnormalities. A completed Phase II, multi-centre, single-arm, open-label study evaluated the efficacy and safety of Revlimid monotherapy treatment for achieving haematopoietic improvement in red blood cell (RBC) transfusion dependent subjects with low- or intermediate-1-risk MDS associated with a deletion 5q cytogenetic abnormality.

63.8% of subjects had achieved RBC-transfusion independence accompanied by a median increase of 5.8 g/dL in blood Hgb concentration from baseline to the maximum value during the response period. Major cytogenetic responses were observed in 44.2% and minor cytogenetic responses were observed in 24.2% of the evaluable subjects. Improvements in bone marrow morphology were also observed. The results of this study demonstrate the efficacy of Revlimid for the treatment of subjects with Low- or Intermediate-1-risk MDS and an associated del 5 cytogenetic abnormality.[15][18][19]

Lenalidomide was approved on 17 June 2013 by the European Medicines Agency for use in low- or intermediate-1-risk myelodysplastic syndromes (MDS) patients who have the deletion 5q cytogenetic abnormality and no other cytogenetic abnormalities, are dependent on red blood cell transfusions, and for whom other treatment options have been found to be insufficient or inadequate.[20]

Mantle cell lymphoma

Lenalidomide is approved by FDA for mantle cell lymphoma in patients whose disease has relapsed or progressed after at least two prior therapies.[1] One of these previous therapies must have included bortezomib.

Other cancers

Lenalidomide is undergoing clinical trial as a treatment for Hodgkin’s lymphoma,[21] as well as non-Hodgkin’s lymphomachronic lymphocytic leukemia and solid tumor cancers, such as carcinoma of the pancreas.[22] One Phase 3 clinical trial being conducted by Celgene in elderly patients with B-cell chronic lymphocytic leukemia was halted in July 2013, when a disproportionate number of cancer deaths were observed during treatment with lenalidomide versus patients treated with chlorambucil.[23]

Adverse effects

In addition to embryo-fetal toxicity, lenalidomide also carries Black Box Warnings for hematologic toxicity (including significant neutropenia and thrombocytopenia) and venous/arterial thromboembolisms.[1]

Serious potential side effects are thrombosispulmonary embolus, and hepatotoxicity, as well as bone marrow toxicity resulting in neutropenia and thrombocytopeniaMyelosuppression is the major dose-limiting toxicity, which is contrary to experience with thalidomide.[24] Lenalidomide may also be associated with adverse effects including second primary malignancy, severe cutaneous reactions, hypersensitivity reactions, tumor lysis syndrome, tumor flare reaction, hypothyroidism, and hyperthyroidism[1]

Teratogenicity

Lenalidomide is related to thalidomide which is known to be teratogenic. Tests in monkeys have suggested lenalidomide is also teratogenic.[25] It therefore has the pregnancy category X and cannot be prescribed for women who are pregnant or who may become pregnant during therapy. For this reason, the drug is only available in the United States(under the brand name Revlimid) through a restricted distribution system called RevAssist. Females who may become pregnant must use at least two forms of reliable contraception during treatment and for at least four weeks after discontinuing treatment with lenalidomide.[1]

Venous thromboembolism

Lenalidomide, like its parent compound thalidomide, may cause venous thromboembolism (VTE), a potentially serious complication with their use. Bennett et al. have reviewed incidents of lenalidomide-associated VTE among patients with multiple myeloma.[26] They have found that there are high rates of VTE when patients with multiple myeloma received thalidomide or lenalidomide in conjunction with dexamethasonemelphalan, or doxorubicin. When lenalidomide and dexamethasone are used to treat multiple myeloma, a median of 14% of patients had VTE (range,3-75%). In patients who took prophylaxis to treat lenalidomide-associated VTE, such as aspirin, thromboembolism rates were found to be lower than without prophylaxis, frequently lower than 10%. Clearly, thromboembolism is a serious adverse drug reaction associated with lenalidomide, as well as thalidomide. In fact, a black box warning is included in the package insert for lenalidomide, indicating that lenalidomide-dexamethasone treatment for multiple myeloma is complicated by high rates of thromboembolism.

Currently,[when?] clinical trials are under way to further test the efficacy of lenalidomide to treat multiple myeloma, and to determine how to prevent lenalidomide-associated venous thromboembolism.[citation needed]

Stevens-Johnson syndrome

In March 2008, the U.S. Food and Drug Administration (FDA) included lenalidomide on a list of 20 prescription drugs under investigation for potential safety problems. The drug is being investigated for possibly increasing the risk of developing Stevens–Johnson syndrome, a life-threatening condition affecting the skin.[27]

FDA ongoing safety review

As of 2011, the FDA has initiated an ongoing review which will focus on clinical trials which found an increased risk of developing cancers such as acute myelogenous leukemia (AML) and B-cell lymphoma,[3] though the FDA is currently advising all people to continue their treatment.[28]

Mechanism of action

Lenalidomide has been used to successfully treat both inflammatory disorders and cancers in the past ten years.[when?] There are multiple mechanisms of action, and they can be simplified by organizing them as mechanisms of action in vitro and in vivo.[29] In vitro, lenalidomide has three main activities: direct anti-tumor effect, inhibition of angiogenesis, and immunomodulationIn vivo, lenalidomide induces tumor cell apoptosis directly and indirectly by inhibition of bone marrow stromal cell support, by anti-angiogenic and anti-osteoclastogenic effects, and by immunomodulatory activity. Lenalidomide has a broad range of activities that can be exploited to treat many hematologic and solid cancers.

On a molecular level, lenalidomide has been shown to interact with the ubiquitin E3 ligase cereblon[30] and target this enzyme to degrade the Ikaros transcription factors IKZF1 and IKZF3.[31] This mechanism was unexpected as it suggests that the major action of lenalidomide is to re-target the activity of an enzyme rather than block the activity of an enzyme or signaling process, and thereby represents a novel mode of drug action. A more specific implication of this mechanism is that the teratogenic and anti-neoplastic properties of lenalidomide, and perhaps other thalidomide derivatives, could be disassociated.

Research

The low level of research that continued on thalidomide, in spite of its scandalous history of teratogenicity, unexpectedly showed that the compound affected immune function. The drug was, for example, recently approved by the FDA for treatment of complications from leprosy; it has also been investigated as an adjunct for treating some malignancies. Recent research on related compounds has revealed a series of molecules which inhibit tumor necrosis factor (TNF-α).[citation needed]

Price

Lenalidomide costs $163,381 per year for the average person in the United States.[3] Lenalidomide made almost $9.7bn for Celgene in 2018.[32]

In 2013, the UK National Institute for Health and Care Excellence (NICE) rejected lenalidomide for “use in the treatment of people with a specific type of the bone marrow disorder myelodysplastic syndrome (MDS)” in England and Scotland, arguing that Celgene “did not provide enough evidence to justify the £3,780 per month (USD$5746.73) price-tag of lenalidomide for use in the treatment of people with a specific type of the bone marrow disorder myelodysplastic syndrome (MDS)”.[33]

SYN

https://link.springer.com/article/10.1007/s10593-015-1670-0

A new process for the synthesis of anticancer drug lenalidomide was developed, using platinum group metal-free and efficient reduction of nitro group with the iron powder and ammonium chloride. It was found that the bromination of the key raw material, methyl 2-methyl-3-nitrobenzoate, could be carried out in chlorine-free solvent methyl acetate without forming significant amounts of hazardous by-products. We also have compared the known synthetic methods for cyclization of methyl 2-(bromomethyl)-3-nitrobenzoate and 3-aminopiperidinedione to form lenalidomide nitro precursor.

SYN

File:Lenalidomide synthesis.png

SYN

EP 0925294; US 5635517; WO 9803502

Cyclization of N-(benzyloxycarbonyl)glutamine (I) by means of CDI in refluxing THF gives 3-(benzyloxycarbonylamino)piperidine-2,6-dione (II), which is deprotected with H2 over Pd/C in ethyl acetate/4N HCl to yield 3-aminopiperidine-2,6-dione hydrochloride (III). Bromination of 2-methyl-3-nitrobenzoic acid methyl ester (IV) with NBS in CCl4 provides 2-(bromomethyl)-3-nitrobenzoic acid methyl ester (V), which is cyclized with the aminopiperidine (III) by means of triethylamine in hot DMF to afford 3-(4-nitro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (VI). Finally, the nitro group of compound (VI) is reduced with H2 over Pd/C in methanol (1, 2).

 

SYN

Bioorg Med Chem Lett 1999,9(11),1625

Treatment of 3-nitrophthalimide (I) with ethyl chloroformate and triethylamine produced 3-nitro-N-(ethoxycarbonyl)phthalimide (II), which was condensed with L-glutamine tert-butyl ester hydrochloride (III) to afford the phthaloyl glutamine derivative (IV). Acidic cleavage of the tert-butyl ester of (IV) provided the corresponding carboxylic acid (V). This was cyclized to the required glutarimide (VI) upon treatment with thionyl chloride and then with triethylamine. The nitro group of (VI) was finally reduced to amine by hydrogenation over Pd/C.

Lenalidomide

    • Synonyms:CC-5013, CDC 501
    • ATC:L04AX04
  • Use:myelodysplastic syndrome (MDS)
  • Chemical name:3-(4-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-2,6-piperidinedione
  • Formula:C13H13N3O3
  • MW:259.27 g/mol
  • CAS-RN:191732-72-6
  • InChI Key:GOTYRUGSSMKFNF-JTQLQIEISA-N
  • InChI:InChI=1S/C13H13N3O3/c14-9-3-1-2-7-8(9)6-16(13(7)19)10-4-5-11(17)15-12(10)18/h1-3,10H,4-6,14H2,(H,15,17,18)/t10-/m0/s1

Synthesis

Trade Names

Country Trade Name Vendor Annotation
D Revlimid Celgene
GB Revlimid Celgene
USA Revlimid Celgene ,2005

Formulations

  • cps. 5 mg, 10 mg

References

    • WO 9 803 502 (Celgene; 29.1.1998; USA-prior. 24.7.1996).
    • WO 2 006 028 964 (Celgene; 16.3.2006; USA-prior. 3.9.2004).
    • US 5 635 517 (Celgene; 3.6.1997; USA-prior. 24.7.1996).
  • medical use for treatment of certain leukemias:

    • US 2 006 030 594 (Celgene; 9.2.2006; USA-prior. 4.10.2005).
  • alternative preparation of III:

    • WO 2 005 005 409 (Siegfried Ltd.; 20.1.2005; CH-prior. 9.7.2003).

References

  1. Jump up to:a b c d e REVLIMID [package insert]. Summit, NJ: Celgene Corporation; 2017. Accessed at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021880s055lbl.pdf on 14 September 2018.
  2. ^ McCarthy PL, Owzar K, Hofmeister CC, et al. (2012). “Lenalidomide after stem-cell transplantation for multiple myeloma”N. Engl. J. Med366 (19): 1770–81. doi:10.1056/NEJMoa1114083PMC 3744390PMID 22571201.
  3. Jump up to:a b c Badros AZ (10 May 2012). “Lenalidomide in Myeloma — A High-Maintenance Friend”. N Engl J Med366 (19): 1836–1838. doi:10.1056/NEJMe1202819PMID 22571206.
  4. ^ “World Health Organization model list of essential medicines: 21st list 2019”. 2019. hdl:10665/325771.
  5. ^ Armoiry X, Aulagner G, Facon T (June 2008). “Lenalidomide in the treatment of multiple myeloma: a review”. Journal of Clinical Pharmacy and Therapeutics33 (3): 219–26. doi:10.1111/j.1365-2710.2008.00920.xPMID 18452408.
  6. Jump up to:a b Li S, Gill N, Lentzsch S (November 2010). “Recent advances of IMiDs in cancer therapy”. Curr Opin Oncol22 (6): 579–85. doi:10.1097/CCO.0b013e32833d752cPMID 20689431.
  7. ^ Tageja N (March 2011). “Lenalidomide – current understanding of mechanistic properties”. Anti-Cancer Agents Med. Chem11 (3): 315–26. doi:10.2174/187152011795347487PMID 21426296.
  8. ^ Kotla V, Goel S, Nischal S, et al. (August 2009). “Mechanism of action of lenalidomide in hematological malignancies”J Hematol Oncol2: 36. doi:10.1186/1756-8722-2-36PMC 2736171PMID 19674465.
  9. ^ Yang B, Yu RL, Chi XH, et al. (2013). “Lenalidomide treatment for multiple myeloma: systematic review and meta-analysis of randomized controlled trials”PLoS ONE8 (5): e64354. doi:10.1371/journal.pone.0064354PMC 3653900PMID 23691202.
  10. ^ Dimopoulos MA, Richardson PG, Brandenburg N, et al. (22 March 2012). “A review of second primary malignancy in patients with relapsed or refractory multiple myeloma treated with lenalidomide”. Blood119 (12): 2764–7. doi:10.1182/blood-2011-08-373514PMID 22323483.
  11. ^ “FDA approves lenalidomide oral capsules (Revlimid) for use in combination with dexamethasone in patients with multiple myeloma”Food and Drug Administration (FDA). 29 June 2006. Retrieved 15 October 2015.
  12. ^ “Approved Drugs – Lenalidomide (Revlimid)”Food and Drug Administration (FDA).
  13. ^ “REVLIMID Receives Positive Final Appraisal Determination from National Institute for Health and Clinical Excellence (NICE) for Use in the National Health Service (NHS) in England and Wales”. Reuters. 23 April 2009.
  14. ^ Ness, Stacey (13 March 2014). “New Specialty Drugs”. Pharmacy Times. Retrieved 5 November 2015.
  15. Jump up to:a b List A, Kurtin S, Roe DJ, et al. (February 2005). “Efficacy of lenalidomide in myelodysplastic syndromes”. The New England Journal of Medicine352 (6): 549–57. doi:10.1056/NEJMoa041668PMID 15703420.
  16. ^ “PDGFRB platelet derived growth factor receptor beta [Homo sapiens (human)] – Gene – NCBI”.
  17. ^ Nimer SD (2006). “Clinical management of myelodysplastic syndromes with interstitial deletion of chromosome 5q”. Journal of Clinical Oncology24 (16): 2576–82. doi:10.1200/JCO.2005.03.6715PMID 16735711.
  18. ^ List AF (August 2005). “Emerging data on IMiDs in the treatment of myelodysplastic syndromes (MDS)”. Seminars in Oncology32 (4 Suppl 5): S31–5. doi:10.1053/j.seminoncol.2005.06.020PMID 16085015.
  19. ^ List A, Dewald G, Bennett J, et al. (October 2006). “Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion”. The New England Journal of Medicine355 (14): 1456–65. doi:10.1056/NEJMoa061292PMID 17021321.
  20. ^ “Revlimid Approved In Europe For Use In Myelodysplastic Syndromes”. The MDS Beacon. Retrieved 17 June 2013.
  21. ^ “Phase II Study of Lenalidomide for the Treatment of Relapsed or Refractory Hodgkin’s Lymphoma”ClinicalTrials.gov. US National Institutes of Health. February 2009.
  22. ^ “276 current clinical trials world-wide, both recruiting and fully enrolled, as of 27 February 2009”ClinicalTrials.gov. US National Institutes of Health. February 2009.
  23. ^ “Celgene Discontinues Phase 3 Revlimid Study after ‘Imbalance’ of Deaths”. Nasdaq. 18 July 2013.
  24. ^ Rao KV (September 2007). “Lenalidomide in the treatment of multiple myeloma”. American Journal of Health-System Pharmacy64 (17): 1799–807. doi:10.2146/ajhp070029PMID 17724360.
  25. ^ “Revlimid Summary of Product Characteristics. Annex I” (PDF)European Medicines Agency. 2012. p. 6.
  26. ^ Bennett CL, Angelotta C, Yarnold PR, et al. (December 2006). “Thalidomide- and lenalidomide-associated thromboembolism among patients with cancer”. JAMA: The Journal of the American Medical Association296 (21): 2558–60. doi:10.1001/jama.296.21.2558-cPMID 17148721.
  27. ^ “Potential Signals of Serious Risks/New Safety Information Identified from the Adverse Event Reporting System (AERS) between January – March 2008”Food and Drug Administration (FDA). March 2008.
  28. ^ “FDA Drug Safety Communication: Ongoing safety review of Revlimid (lenalidomide) and possible increased risk of developing new malignancies”Food and Drug Administration(FDA). April 2011.
  29. ^ Vallet S, Palumbo A, Raje N, et al. (July 2008). “Thalidomide and lenalidomide: Mechanism-based potential drug combinations”. Leukemia & Lymphoma49 (7): 1238–45. doi:10.1080/10428190802005191PMID 18452080.
  30. ^ Zhu YX, Braggio E, Shi CX, et al. (2011). “Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide”Blood118 (18): 4771–9. doi:10.1182/blood-2011-05-356063PMC 3208291PMID 21860026.
  31. ^ Stewart AK (2014). “Medicine. How thalidomide works against cancer”Science343(6168): 256–7. doi:10.1126/science.1249543PMC 4084783PMID 24436409.
  32. ^ “Top 10 Best-Selling Cancer Drugs of 2018”. Genetic Engineering and Biotechnology News. 22 April 2019. Retrieved 25 April 2019.
  33. ^ “Revlimid faces NICE rejection for use in rare blood cancer Watchdog’s draft guidance does not recommend Celgene’s drug for NHS use in England and Wales”. Pharma News. 11 July 2013. Retrieved 5 November 2015.

Further reading

External links

Lenalidomide
Lenalidomide enantiomers.svg
Clinical data
Pronunciation /ˌlɛnəˈlɪdmd/
Trade names Revlimid
AHFS/Drugs.com Monograph
MedlinePlus a608001
License data
Pregnancy
category
  • AU: X (High risk)
  • US: X(Contraindicated)
Routes of
administration
Oral (capsules)
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability Undetermined
Protein binding 30%
Metabolism Undetermined
Elimination half-life 3 hours
Excretion Renal (67% unchanged)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard(EPA)
ECHA InfoCard 100.218.924 Edit this at Wikidata
Chemical and physical data
Formula C13H13N3O3
Molar mass 259.261 g/mol g·mol−1
3D model (JSmol)
Chirality Racemic mixture

//////////LENALIDOMIDE, レナリドミド ,REVLIMID, Celgene Corporation, леналидомид ليناليدوميد 来那度胺 

%d bloggers like this: