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ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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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 PHARMACEUTICALS 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 year tenure till date Dec 2017, 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, 50 Lakh plus views on dozen plus blogs, 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 19 lakh plus views on New Drug Approvals Blog in 216 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

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BQ-788


BQ-788.svg

ChemSpider 2D Image | BQ-788 | C34H50N5NaO7

Image result for bq-788

Image result for bq-788

BQ-788

  • Molecular FormulaC34H50N5NaO7
  • Average mass663.780 Da

SP ROT +3.8 ° Conc: 1.032 g/100mL; methanol; Wavlenght: 589.3 nm, Development of an efficient strategy for the synthesis of the ETB receptor antagonist BQ-788 and some related analogues
Peptides (New York, NY, United States) (2005), 26, (8), 1441-1453., https://doi.org/10.1016/j.peptides.2005.03.022

FOR FREE FORM +19.6 °, Conc: 0.998 g/100mL; : N,N-dimethylformamide; 589.3 nm

CAS 156161-89-6 [RN]
CAS 173326-37-9 FREE ACID
2,6-Dimethylpiperidinecarbonyl-γ-Methyl-Leu-Nin-(Methoxycarbonyl)-D-Trp-D-Nle
BQ 788 sodium salt
BQ788
D-Norleucine, N-(((2R,6S)-2,6-dimethyl-1-piperidinyl)carbonyl)-4-methyl-L-leucyl-1-(methoxycarbonyl)-D-tryptophyl-, monosodium salt
D-Norleucine, N-((cis-2,6-dimethyl-1-piperidinyl)carbonyl)-4-methyl-L-leucyl-1-(methoxycarbonyl)-D-tryptophyl-, monosodium salt
D-Norleucine, N-[[(2R,6S)-2,6-dimethyl-1-piperidinyl]carbonyl]-4-methyl-L-leucyl-1-(methoxycarbonyl)-D-tryptophyl-, sodium salt (1:1)
MFCD00797882
N-[N-[N-[(2,6-Dimethyl-1-piperidinyl)carbonyl]-4-methyl-L-leucyl]-1-(methoxycarbonyl)-D-tryptophyl]-D-norleucine sodium salt
 
Sodium N-{[(2R,6S)-2,6-dimethylpiperidin-1-yl]carbonyl}-4-methyl-L-leucyl-N-[(1R)-1-carboxylatopentyl]-1-(methoxycarbonyl)-D-tryptophanamide
2,6-Dimethylpiperidinecarbonyl-γ-Methyl-Leu-Nin-(Methoxycarbonyl)-D-Trp-D-Nle

BQ-788 is a selective ETB antagonist.[1]

presumed to be under license from Banyu , was investigating BQ-788, a selective endothelin receptor B (ETRB) antagonist, for treating metastatic melanoma. By December 2009, the drug was in validation.

Also claimed is their use as an ETBR antagonist and for treating cancers, such as brain cancer, pancreas cancer, colon cancer, breast cancer, ovary cancer, prostate cancer, glioblastoma, solid tumor, melanoma and squamous cell carcinoma. Represent a first filing from ENB Therapeutics Inc and the inventors on these deuterated forms of BQ-788. Melcure SarL ,

SYN

By Brosseau, Jean-Philippe et alFrom Peptides (New York, NY, United States), 26(8), 1441-1453; 2005

CONTD…………

PAPER

https://pubs.acs.org/doi/pdf/10.1021/jo00130a028

N-(cw-2,6-Dimethylpiperidinocarbonyl)-y-methylleucylD-l-(methoxycarbonyl)tryptophanyl-D-norleucine Sodium Salt (1, BQ-788). To a solution of 15 (3.5 g, 5.5 mmol) in methanol (50 mL) was slowly added 5% aqueous NaHCOs (300 mL) over a period of 30 min. The solution was stirred until clarity was achieved (30 min, 23 °C). The solution was diluted with water (200 mL), and the resulting solution was passed through a C18 (60 mL) cartridge preequilbrated in water. BQ-788 (1) was eluted with methanol (2 x 50 mL), concentrated under reduced pressure, resuspended in water (50 mL), and lyophilized to quantitatively yield compound 1 as a white powder:

HPLC £r = 16.4 (gradient A, > 99%);

NMR (400 MHz, DMSO-d6) ó 0.80 (s, 9H), 0.74-0.85 (m, 3H), 1.00 (d, 3H), 1.02 (d, 3H), 1.10-1.25 (m, 6H), 1.30-1.55 (m, 6H), 1.60-1.75 (m, 2H), 2.92 (dd, 1H), 3.12 (dd, 1H), 3.78 (m, 1H), 3.95 (s, 3H), 4.08 (m, 1H), 4.13 (m, 1H), 4.29 (m, 1H), 4.50 (m, 1H), 5.98 (d, 1H), 7.22 (t, 1H), 7.32 (t, 1H), 7.50 (s, 1H), 7.58 (br d, 1H), 7.65 (d, 1H), 8.05 (d, 1H), 8.15 (br d, 1H) ESMS m/z 640.6 (M).

PATENT

WO-2019140324

Novel deuterated analogs of a substituted heterocyclic compound, particularly BQ-788 , processes for their preparation and compositions and combinations comprising them are claimed.

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019140324&tab=PCTDESCRIPTION&_cid=P22-JYJK98-13819-1

PAPER

https://www.sciencedirect.com/science/article/abs/pii/S0196978105001415

Image result for bq-788

PAPER

By He, John X.; Cody, Wayne L.; Doherty, Annette M., From Journal of Organic Chemistry (1995), 60(25), 8262-6

Journal of medicinal chemistry (1996), 39(12), 2313-30.

References

  1. ^ Okada, M; Nishikibe, M (Winter 2002). “BQ-788, a selective endothelin ET(B) receptor antagonist”. Cardiovascular drug reviews20 (1): 53–66. PMID 12070534.
BQ-788
BQ-788.svg
Names
Systematic IUPAC name

Sodium N-{[(2R,6S)-2,6-dimethyl-1-piperidinyl]carbonyl}-4-methyl-L-leucyl-N-[(1R)-1-carboxylatopentyl]-1-(methoxycarbonyl)-D-tryptophanamide
Identifiers
3D model (JSmol)
ChemSpider
PubChem CID
Properties
C34H50N5NaO7
Molar mass 663.792 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

///////////BQ-788, BQ 788, BQ788, ETBR antagonist, cancers,  brain cancer, pancreas cancer, colon cancer, breast cancer, ovary cancer, prostate cancer, glioblastoma, solid tumor, melanoma, squamous cell carcinoma, PEPTIDE

CCCC[C@H](C(=O)O)NC(=O)[C@@H](Cc1cn(c2c1cccc2)C(=O)OC)NC(=O)[C@H](CC(C)(C)C)NC(=O)N3[C@@H](CCC[C@@H]3C)C

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Caplacizumab-yhdp, カプラシズマブ


FDA approves first therapy Cablivi (caplacizumab-yhdp) カプラシズマブ  , for the treatment of adult patients with a rare blood clotting disorder

FDA

February 6, 2019

The U.S. Food and Drug Administration today approved Cablivi (caplacizumab-yhdp) injection, the first therapy specifically indicated, in combination with plasma exchange and immunosuppressive therapy, for the treatment of adult patients with acquired thrombotic thrombocytopenic purpura (aTTP), a rare and life-threatening disorder that causes blood clotting.

“Patients with aTTP endure hours of treatment with daily plasma exchange, which requires being attached to a machine that takes blood out of the body and mixes it with donated plasma and then returns it to the body. Even after days or weeks of this treatment, as well as taking drugs that suppress the immune system, many patients will have a recurrence of aTTP,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Cablivi is the first targeted treatment that inhibits the formation of blood clots. It provides a new treatment option for patients that may reduce recurrences.”

Patients with aTTP develop extensive blood clots in the small blood vessels throughout the body. These clots can cut off oxygen and blood supply to the major organs and cause strokes and heart attacks that may lead to brain damage or death. Patients can develop aTTP because of conditions such as cancer, HIV, pregnancy, lupus or infections, or after having surgery, bone marrow transplantation or chemotherapy.

The efficacy of Cablivi was studied in a clinical trial of 145 patients who were randomized to receive either Cablivi or a placebo. Patients in both groups received the current standard of care of plasma exchange and immunosuppressive therapy. The results of the trial demonstrated that platelet counts improved faster among patients treated with Cablivi, compared to placebo. Treatment with Cablivi also resulted in a lower total number of patients with either aTTP-related death and recurrence of aTTP during the treatment period, or at least one treatment-emergent major thrombotic event (where blood clots form inside a blood vessel and may then break free to travel throughout the body).The proportion of patients with a recurrence of aTTP in the overall study period (the drug treatment period plus a 28-day follow-up period after discontinuation of drug treatment) was lower in the Cablivi group (13 percent) compared to the placebo group (38 percent), a finding that was statistically significant.

Common side effects of Cablivi reported by patients in clinical trials were bleeding of the nose or gums and headache. The prescribing information for Cablivi includes a warning to advise health care providers and patients about the risk of severe bleeding.

Health care providers are advised to monitor patients closely for bleeding when administering Cablivi to patients who currently take anticoagulants.

The FDA granted this application Priority Review designation. Cablivi also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted the approval of Cablivi to Ablynx.

 EU

Cablivi is the first therapeutic approved in Europe, for the treatment of a rare blood-clotting disorder

On September 03, 2018, the European Commission has granted marketing authorization for Cablivi™ (caplacizumab) for the treatment of adults experiencing an episode of acquired thrombotic thrombocytopenic purpura (aTTP), a rare blood-clotting disorder. Cablivi is the first therapeutic specifically indicated for the treatment of aTTP   1. Cablivi was designated an ‘orphan medicine’ (a medicine used in rare diseases) on April 30, 2009. The approval of Cablivi in the EU is based on the Phase II TITAN and Phase III HERCULES studies in 220 adult patients with aTTP. The efficacy and safety of caplacizumab in addition to standard-of-care treatment, daily PEX and immunosuppression, were demonstrated in these studies. In the HERCULES study, treatment with caplacizumab in addition to standard-of-care resulted in a significantly shorter time to platelet count response (p<0.01), the study’s primary endpoint; a significant reduction in aTTP-related death, recurrence of aTTP, or at least one major thromboembolic event during study drug treatment (p<0.0001); and a significantly lower number of aTTP recurrences in the overall study period (p<0.001). Importantly, treatment with caplacizumab resulted in a clinically meaningful reduction in the use of PEX and length of stay in the intensive care unit (ICU) and the hospital, compared to the placebo group. Cablivi was developed by Ablynx, a Sanofi company. Sanofi Genzyme, the specialty care global business unit of Sanofi, will work with relevant local authorities to make Cablivi available to patients in need in countries across Europe.

About aTTP aTTP is a life-threatening, autoimmune blood clotting disorder characterized by extensive clot formation in small blood vessels throughout the body, leading to severe thrombocytopenia (very low platelet count), microangiopathic hemolytic anemia (loss of red blood cells through destruction), ischemia (restricted blood supply to parts of the body) and widespread organ damage especially in the brain and heart. About Cablivi Caplacizumab blocks the interaction of ultra-large von Willebrand Factor (vWF) multimers with platelets and, therefore, has an immediate effect on platelet adhesion and the ensuing formation and accumulation of the micro-clots that cause the severe thrombocytopenia, tissue ischemia and organ dysfunction in aTTP   2.

Note – Caplacizumab is a bivalent anti-vWF Nanobody that received Orphan Drug Designation in Europe and the United States in 2009, in Switzerland in 2017 and in Japan in 2018. The U.S. Food and Drug Administration (FDA) has accepted for priority review the Biologics License Application for caplacizumab for treatment of adults experiencing an episode of aTTP. The target action date for the FDA decision is February 6, 2019

http://hugin.info/152918/R/2213684/863478.pdf

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/004426/WC500255075.pdf

Image result for Caplacizumab

More………….

EVQLVESGGG LVQPGGSLRL SCAASGRTFS YNPMGWFRQA PGKGRELVAA ISRTGGSTYY
PDSVEGRFTI SRDNAKRMVY LQMNSLRAED TAVYYCAAAG VRAEDGRVRT LPSEYTFWGQ
GTQVTVSSAA AEVQLVESGG GLVQPGGSLR LSCAASGRTF SYNPMGWFRQ APGKGRELVA
AISRTGGSTY YPDSVEGRFT ISRDNAKRMV YLQMNSLRAE DTAVYYCAAA GVRAEDGRVR
TLPSEYTFWG QGTQVTVSS
(disulfide bridge: 22-96, 153-227)

Sequence:

1EVQLVESGGG LVQPGGSLRL SCAASGRTFS YNPMGWFRQA PGKGRELVAA
51ISRTGGSTYY PDSVEGRFTI SRDNAKRMVY LQMNSLRAED TAVYYCAAAG
101VRAEDGRVRT LPSEYTFWGQ GTQVTVSSAA AEVQLVESGG GLVQPGGSLR
151LSCAASGRTF SYNPMGWFRQ APGKGRELVA AISRTGGSTY YPDSVEGRFT
201ISRDNAKRMV YLQMNSLRAE DTAVYYCAAA GVRAEDGRVR TLPSEYTFWG
251QGTQVTVSS

EU 2018/8/31 APPROVED, Cablivi

Treatment of thrombotic thrombocytopenic purpura, thrombosis

Immunoglobulin, anti-(human von Willebrand’s blood-coagulation factor VIII domain A1) (human-Lama glama dimeric heavy chain fragment PMP12A2h1)

Other Names

  • 1: PN: WO2011067160 SEQID: 1 claimed protein
  • 98: PN: WO2006122825 SEQID: 98 claimed protein
  • ALX 0081
  • ALX 0681
  • Caplacizumab
FORMULA
C1213H1891N357O380S10
CAS
915810-67-2
MOL WEIGHT
27875.8075

Caplacizumab (ALX-0081) (INN) is a bivalent VHH designed for the treatment of thrombotic thrombocytopenic purpura and thrombosis.[1][2]

This drug was developed by Ablynx NV.[3] On 31 August 2018 it was approved in the European Union for the “treatment of adults experiencing an episode of acquired thrombotic thrombocytopenic purpura (aTTP), in conjunction with plasma exchange and immunosuppression”.[4]

It is an anti-von Willebrand factor humanized immunoglobulin.[5] It acts by blocking platelet aggregation to reduce organ injury due to ischemia.[5] Results of the phase II TITAN trial have been reported.[5]

In February 2019, caplacizumab-yhdp (CABLIVI, Ablynx NV) has been approved by the Food and Drug Administration for treatment of adult patients with acquired thrombotic thrombocytopenic purpura (aTTP). The drug is used in combination with plasma exchange and immunosuppressive therapy. [6]

PATENTS

WO 2006122825

WO 2009115614

WO 2011067160

WO 2011098518

WO 2011162831

WO 2013013228

WO 2014109927

WO 2016012285

WO 2016138034

WO 2016176089

WO 2017180587

WO 2017186928

WO 2018067987

Image result for Caplacizumab

Caplacizumab
Monoclonal antibody
Type Single domain antibody
Source Humanized
Target VWF
Clinical data
Synonyms ALX-0081
ATC code
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
Chemical and physical data
Formula C1213H1891N357O380S10
Molar mass 27.88 kg/mol

CLIP

https://www.tandfonline.com/doi/full/10.1080/19420862.2016.1269580

Caplacizumab (ALX-0081) is a humanized single-variable-domain immunoglobulin (Nanobody) that targets von Willebrand factor, and thereby inhibits the interaction between von Willebrand factor multimers and platelets. In a Phase 2 study (NCT01151423) of 75 patients with acquired thrombotic thrombocytopenic purpura who received SC caplacizumab (10 mg daily) or placebo during plasma exchange and for 30 d afterward, the time to a response was significantly reduced with caplacizumab compared with placebo (39% reduction in median time, P = 0.005).39Peyvandi FScully MKremer Hovinga JACataland SKnöbl PWu HArtoni AWestwood JPMansouri Taleghani MJilma B, et al. Caplacizumab for acquired thrombotic thrombocytopenic purpura. N Engl J Med 2016; 374(6):51122; PMID:26863353; http://dx.doi.org/10.1056/NEJMoa1505533[Crossref][PubMed][Web of Science ®][Google Scholar] The double-blind, placebo-controlled, randomized Phase 3 HERCULES study (NCT02553317) study will evaluate the efficacy and safety of caplacizumab treatment in more rapidly curtailing ongoing microvascular thrombosis when administered in addition to standard of care treatment in subjects with an acute episode of acquired thrombotic thrombocytopenic purpura. Patients will receive an initial IV dose of either caplacizumab or placebo followed by daily SC injections for a maximum period of 6 months. The primary outcome measure is the time to platelet count response. The estimated enrollment is 92 patients, and the estimated primary completion date of the study is October 2017. A Phase 3 follow-up study (NCT02878603) for patients who completed the HERCULES study is planned.

References

///////////////caplacizumab, Cablivi,  Ablynx, Priority Review, Orphan Drug designation,  fda 2019, eu 2018, Caplacizumab, nti-vWF Nanobody, Orphan Drug Designation, aTTP, Cablivi, Ablynx, Sanofi , ALX-0081, カプラシズマブ  , PEPTIDE, ALX 0081

Elapegademase, エラペグアデマーゼ (遺伝子組換え)


AQTPAFNKPK VELHVHLDGA IKPETILYYG RKRGIALPAD TPEELQNIIG MDKPLSLPEF
LAKFDYYMPA IAGSREAVKR IAYEFVEMKA KDGVVYVEVR YSPHLLANSK VEPIPWNQAE
GDLTPDEVVS LVNQGLQEGE RDFGVKVRSI LCCMRHQPSW SSEVVELCKK YREQTVVAID
LAGDETIEGS SLFPGHVKAY AEAVKSGVHR TVHAGEVGSA NVVKEAVDTL KTERLGHGYH
TLEDTTLYNR LRQENMHFEV CPWSSYLTGA WKPDTEHPVV RFKNDQVNYS LNTDDPLIFK
STLDTDYQMT KNEMGFTEEE FKRLNINAAK SSFLPEDEKK ELLDLLYKAY GMPSPA

str1

>>Elapegademase<<<
AQTPAFNKPKVELHVHLDGAIKPETILYYGRKRGIALPADTPEELQNIIGMDKPLSLPEF
LAKFDYYMPAIAGSREAVKRIAYEFVEMKAKDGVVYVEVRYSPHLLANSKVEPIPWNQAE
GDLTPDEVVSLVNQGLQEGERDFGVKVRSILCCMRHQPSWSSEVVELCKKYREQTVVAID
LAGDETIEGSSLFPGHVKAYAEAVKSGVHRTVHAGEVGSANVVKEAVDTLKTERLGHGYH
TLEDTTLYNRLRQENMHFEVCPWSSYLTGAWKPDTEHPVVRFKNDQVNYSLNTDDPLIFK
STLDTDYQMTKNEMGFTEEEFKRLNINAAKSSFLPEDEKKELLDLLYKAYGMPSPA

ChemSpider 2D Image | ELAPEGADEMASE | C10H20N2O5

Elapegademase, エラペグアデマーゼ (遺伝子組換え)

EZN-2279

Protein chemical formula C1797H2795N477O544S12

Protein average weight 115000.0 Da

Peptide

APPROVED, FDA, Revcovi, 2018/10/5

CAS: 1709806-75-6

Elapegademase-lvlr, Poly(oxy-1,2-ethanediyl), alpha-carboxy-omega-methoxy-, amide with adenosine deaminase (synthetic)

L-Lysine, N6-[(2-methoxyethoxy)carbonyl]-
N6-[(2-Methoxyethoxy)carbonyl]-L-lysine

EZN-2279; PEG-rADA; Pegademase recombinant – Leadiant Biosciences; Pegylated recombinant adenosine deaminase; Polyethylene glycol recombinant adenosine deaminase; STM-279, UNII: 9R3D3Y0UHS

  • Originator Sigma-Tau Pharmaceuticals
  • Developer Leadiant Biosciences; Teijin Pharma
  • Class Antivirals; Polyethylene glycols
  • Mechanism of Action Adenosine deaminase stimulants
  • Orphan Drug Status Yes – Immunodeficiency disorders; Adenosine deaminase deficiency
  • Registered Adenosine deaminase deficiency; Immunodeficiency disorders
  • 05 Oct 2018 Registered for Adenosine deaminase deficiency (In adults, In children) in USA (IM)
  • 05 Oct 2018 Registered for Immunodeficiency disorders (In adults, In children) in USA (IM)
  • 04 Oct 2018 Elapegademase receives priority review status for Immunodeficiency disorders and Adenosine deaminase deficiency in USA

検索キーワード:Elapegademase (Genetical Recombination)
検索件数:1


エラペグアデマーゼ(遺伝子組換え)
Elapegademase (Genetical Recombination)

[1709806-75-6]

Elapegademase is a PEGylated recombinant adenosine deaminase. It can be defined molecularly as a genetically modified bovine adenosine deaminase with a modification in cysteine 74 for serine and with about 13 methoxy polyethylene glycol chains bound via carbonyl group in alanine and lysine residues.[4] Elapegademase is generated in E. coli, developed by Leadiant Biosciences and FDA approved on October 5, 2018.[15]

Indication

Elapegademase is approved for the treatment of adenosine deaminase severe combined immune deficiency (ADA-SCID) in pediatric and adult patients.[1] This condition was previously treated by the use of pegamedase bovine as part of an enzyme replacement therapy.[2]

ADA-SCID is a genetically inherited disorder that is very rare and characterized by a deficiency in the adenosine deaminase enzyme. The patients suffering from this disease often present a compromised immune system. This condition is characterized by very low levels of white blood cells and immunoglobulin levels which results in severe and recurring infections.[3]

Pharmacodynamics

In clinical trials, elapegademase was shown to increase adenosine deaminase activity while reducing the concentrations of toxic metabolites which are the hallmark of ADA-SCID. As well, it was shown to improve the total lymphocyte count.[6]

Mechanism of action

The ADA-SCID is caused by the presence of mutations in the ADA gene which is responsible for the synthesis of adenosine deaminase. This enzyme is found throughout the body but it is mainly active in lymphocytes. The normal function of adenosine deaminase is to eliminate deoxyadenosine, created when DNA is degraded, by converting it into deoxyinosine. This degradation process is very important as deoxyadenosine is cytotoxic, especially for lymphocytes. Immature lymphocytes are particularly vulnerable as deoxyadenosine kills them before maturation making them unable to produce their immune function.[3]

Therefore, based on the causes of ADA-SCID, elapegademase works by supplementing the levels of adenosine deaminase. Being a recombinant and an E. coli-produced molecule, the use of this drug eliminates the need to source the enzyme from animals, as it was used previously.[1]

Absorption

Elapegademase is administered intramuscularly and the reported Tmax, Cmax and AUC are approximately 60 hours, 240 mmol.h/L and 33000 hr.mmol/L as reported during a week.[Label]

Volume of distribution

This pharmacokinetic property has not been fully studied.

Protein binding

This pharmacokinetic property is not significant as the main effect is in the blood cells.

Metabolism

Metabolism studies have not been performed but it is thought to be degraded by proteases to small peptides and individual amino acids.

Route of elimination

This pharmacokinetic property has not been fully studied.

Half life

This pharmacokinetic property has not been fully studied.

Clearance

This pharmacokinetic property has not been fully studied.

Toxicity

As elapegademase is a therapeutic protein, there is a potential risk of immunogenicity.

There are no studies related to overdose but the highest weekly prescribed dose in clinical trials was 0.4 mg/kg. In nonclinical studies, a dosage of 1.8 fold of the clinical dose produced a slight increase in the activated partial thromboplastin time.[Label]

FDA label. Download (145 KB)

General References

  1. Rare DR [Link]
  2. Globe News Wire [Link]
  3. NIH [Link]
  4. NIHS reports [File]
  5. WHO Drug Information 2017 [File]
  6. Revcovi information [File]

/////////////Elapegademase, Peptide, エラペグアデマーゼ (遺伝子組換え) , EZN-2279, Elapegademase-lvlr, Orphan Drug, STM 279, FDA 2018

COCCOC(=O)NCCCC[C@H](N)C(=O)O

“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This is a compilation for educational purposes only. P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

 

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ANTHONY MELVIN CRASTO

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

 

Calaspargase pegol, カラスパルガーゼペゴル


LPNITILATG GTIAGGGDSA TKSNYTAGKV GVENLVNAVP QLKDIANVKG EQVVNIGSQD
MNDDVWLTLA KKINTDCDKT DGFVITHGTD TMEETAYFLD LTVKCDKPVV MVGAMRPSTS
MSADGPFNLY NAVVTAADKA SANRGVLVVM NDTVLDGRDV TKTNTTDVAT FKSVNYGPLG
YIHNGKIDYQ RTPARKHTSD TPFDVSKLNE LPKVGIVYNY ANASDLPAKA LVDAGYDGIV
SAGVGNGNLY KTVFDTLATA AKNGTAVVRS SRVPTGATTQ DAEVDDAKYG FVASGTLNPQ
KARVLLQLAL TQTKDPQQIQ QIFNQY
(tetramer; disulfide bridge 77-105, 77′-105′, 77”-105”, 77”’-105”’)

Image result for Calaspargase pegol

str3

Calaspargase pegol

Molecular Formula, C1516-H2423-N415-O492-S8 (peptide monomer), Molecular Weight, 10261.2163

APPROVED, Asparlas, FDA 2018/12/20

CAS 941577-06-6

UNII T9FVH03HMZ

カラスパルガーゼペゴル;

(27-Alanine,64-aspartic acid,252-threonine,263-asparagine)-L-asparaginase 2 (EC 3.5.1.1, L-asparagineamidohydrolase II) Escherichia coli (strain K12) tetramer alpha4, carbamates with alpha-carboxy-omega-methoxypoly(oxyethylene)

Asparaginase (Escherichia coli isoenzyme II), conjugate with alpha-(((2,5-dioxo-1-pyrrolidinyl)oxy)carbonyl)-omega-methoxypoly(oxy-1,2-ethanediyl)

List Acronyms
Peptide
  • Calaspargase pegol
  • calaspargase pegol-mknl
  • EZN-2285
  • Used to treat acute lymphoblastic leukemia., Antineoplastic
  • BAX-2303
    SC-PEG E. Coli L-asparaginase
    SHP-663

Calaspargase pegol-mknl (trade name Asparlas) is a drug for the treatment of acute lymphoblastic leukemia (ALL). It is approved by the Food and Drug Administration for use in the United States as a component of a multi-agent chemotherapeutic regimen for ALL in pediatric and young adult patients aged 1 month to 21 years.[1]

Calaspargase pegol was first approved in 2018 in the U.S. as part of a multi-agent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia.

In 2008, orphan drug designation was assigned in the E.U.

Calaspargase pegol is an engineered protein consisting of the E. coli-derived enzyme L-asparaginase II conjugated with succinimidyl carbonate monomethoxypolyethylene glycol (pegol).[2] The L-asparaginase portion hydrolyzes L-asparagine to L-aspartic acid depriving the tumor cell of the L-asparagine it needs for survival.[2] The conjugation with the pegol group increases the half-life of the drug making it longer acting.

Asparaginase is an important agent used to treat acute lymphoblastic leukemia (ALL) [1]. Asparagine is incorporated into most proteins, and the synthesis of proteins is stopped when asparagine is absent, which inhibits RNA and DNA synthesis, resulting in a halt in cellular proliferation. This forms the basis of asparaginase treatment in ALL [1][2][6].

Calaspargase pegol, also known as asparlas, is an asparagine specific enzyme which is indicated as a part of a multi-agent chemotherapy regimen for the treatment of ALL [3]. The asparagine specific enzyme is derived from Escherichia coli, as a conjugate of L-asparaginase (L-asparagine amidohydrolase) and monomethoxypolyethylene glycol (mPEG) with a succinimidyl carbonate (SC) linker to create a stable molecule which increases the half-life and decreases the dosing frequency [Label][1].

Calaspargase pegol, by Shire pharmaceuticals, was approved by the FDA on December 20, 2018 for acute lymphoblastic anemia (ALL) [3].

Indication

This drug is is an asparagine specific enzyme indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of acute lymphoblastic leukemia in pediatric and young adult patients age 1 month to 21 years [Label].

The pharmacokinetics of calaspargase pegol were examined when given in combination with multiagent chemotherapy in 124 patients with B-cell lineage ALL [3]. The FDA approval of this drug was based on the achievement and maintenance of nadir serum asparaginase activity above the level of 0.1 U/mL when administering calaspargase, 2500 U/m2 intravenously, at 3-week intervals.

Associated Conditions

Pharmacodynamics

The effect of this drug is believed to occur by selective killing of leukemic cells due to depletion of plasma L-asparagine. Leukemic cells with low expression of asparagine synthetase are less capable of producing L-asparagine, and therefore rely on exogenous L-asparagine for survival [Label]. When asparagine is depleted, tumor cells cannot proliferate [6].

During remission induction, one dose of SC-PEG (2500 IU/m2) results in a sustained therapeutic serum asparaginase activity (SAA) without excessive toxicity or marked differences in the proportion of patients with low end-induction minimum residual disease (MRD) [5].

Pharmacodynamic (PD) response was studied through measurement of plasma and cerebrospinal fluid (CSF) asparagine concentrations with an LC-MS/MS assay (liquid chromatography–mass spectrometry). Asparagine concentration in plasma was sustained below the assay limit of quantification for more than 18 days after one dose of calaspargase pegol, 2,500 U/m2, during the induction phase of treatment. Average cerebrospinal asparagine concentrations decreased from a pretreatment concentration of 0.8 μg/mL (N=10) to 0.2 μg/mL on Day 4 (N=37) and stayed decreased at 0.2 μg/mL (N=35) 25 days after the administration of one of 2,500 U/m2 in the induction phase [Label].

Mechanism of action

L-asparaginase (the main component of this drug) is an enzyme that catalyzes the conversion of the amino acid L-asparagine into both aspartic acid and ammonia [Label][2]. This process depletes malignant cells of their required asparagine. The depletion of asparagine then blocks protein synthesis and tumor cell proliferation, especially in the G1 phase of the cell cycle. As a result, tumor cell death occurs. Asparagine is important in protein synthesis in acute lymphoblastic leukemia (ALL) cells which, unlike normal cells, cannot produce this amino acid due to lack of the enzyme asparagine synthase [2][Label].

Pegylation decreases enzyme antigenicity and increases its half-life. Succinimidyl carbamate (SC) is used as a PEG linker to facilitate attachment to asparaginase and enhances the stability of the formulation [4][1]. SC-PEG urethane linkages formed with lysine groups are more hydrolytically stable [2].

Toxicity

Pancreatitis, hepatotoxicity, hemorrhage, and thrombosis have been observed with calaspargase pegol use [Label].

Pancreatitis: Discontinue this drug in patients with pancreatitis, and monitor blood glucose.

Hepatotoxicity: Hepatic function should be tested regularly, and trough levels of this drug should be measured during the recovery phase of the drug cycle [Label].

Hemorrhage or Thrombosis: Discontinue this drug in serious or life-threatening hemorrhage or thrombosis. In cases of hemorrhage, identify the cause of hemorrhage and treat appropriately. Administer anticoagulant therapy as indicated in thrombotic events [Label].

A note on hypersensitivity:

Observe the patient for 1 hour after administration of calaspargase pegol for possible hypersensitivity [Label]. In cases of previous hypersensitivity to this drug, discontinue this drug immediately.

Lactation: Advise women not to breastfeed while taking this drug [Label].

Pregnancy: There are no available data on the use of calaspargase pegol in pregnant women to confirm a risk of drug-associated major birth defects and miscarriage. Published literature studies in pregnant animals suggest asparagine depletion can cause harm to the animal offspring. It is therefore advisable to inform women of childbearing age of this risk. The background risk of major birth defects and miscarriage for humans is unknown at this time [Label].

Pregnancy testing should occur before initiating treatment. Advise females of reproductive potential to avoid becoming pregnant while taking this drug. Females should use effective contraceptive methods, including a barrier methods, during treatment and for at least 3 months after the last dose. There is a risk for an interaction between calaspargase pegol and oral contraceptives. The concurrent use of this drug with oral contraceptives should be avoided. Other non-oral contraceptive methods should be used in women of childbearing potential [Label].

References
  1. Angiolillo AL, Schore RJ, Devidas M, Borowitz MJ, Carroll AJ, Gastier-Foster JM, Heerema NA, Keilani T, Lane AR, Loh ML, Reaman GH, Adamson PC, Wood B, Wood C, Zheng HW, Raetz EA, Winick NJ, Carroll WL, Hunger SP: Pharmacokinetic and pharmacodynamic properties of calaspargase pegol Escherichia coli L-asparaginase in the treatment of patients with acute lymphoblastic leukemia: results from Children’s Oncology Group Study AALL07P4. J Clin Oncol. 2014 Dec 1;32(34):3874-82. doi: 10.1200/JCO.2014.55.5763. Epub 2014 Oct 27. [PubMed:25348002]
  2. Appel IM, Kazemier KM, Boos J, Lanvers C, Huijmans J, Veerman AJ, van Wering E, den Boer ML, Pieters R: Pharmacokinetic, pharmacodynamic and intracellular effects of PEG-asparaginase in newly diagnosed childhood acute lymphoblastic leukemia: results from a single agent window study. Leukemia. 2008 Sep;22(9):1665-79. doi: 10.1038/leu.2008.165. Epub 2008 Jun 26. [PubMed:18580955]
  3. Blood Journal: Randomized Study of Pegaspargase (SS-PEG) and Calaspargase Pegol (SPC-PEG) in Pediatric Patients with Newly Diagnosed Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma: Results of DFCI ALL Consortium Protocol 11-001 [Link]

References

  1. ^ “FDA approves longer-acting calaspargase pegol-mknl for ALL” (Press release). Food and Drug Administration. December 20, 2018.
  2. Jump up to:a b “Calaspargase pegol-mknl”NCI Drug Dictionary. National Cancer Institute.

FDA label, Download(300 KB)

General References

  1. Angiolillo AL, Schore RJ, Devidas M, Borowitz MJ, Carroll AJ, Gastier-Foster JM, Heerema NA, Keilani T, Lane AR, Loh ML, Reaman GH, Adamson PC, Wood B, Wood C, Zheng HW, Raetz EA, Winick NJ, Carroll WL, Hunger SP: Pharmacokinetic and pharmacodynamic properties of calaspargase pegol Escherichia coli L-asparaginase in the treatment of patients with acute lymphoblastic leukemia: results from Children’s Oncology Group Study AALL07P4. J Clin Oncol. 2014 Dec 1;32(34):3874-82. doi: 10.1200/JCO.2014.55.5763. Epub 2014 Oct 27. [PubMed:25348002]
  2. Appel IM, Kazemier KM, Boos J, Lanvers C, Huijmans J, Veerman AJ, van Wering E, den Boer ML, Pieters R: Pharmacokinetic, pharmacodynamic and intracellular effects of PEG-asparaginase in newly diagnosed childhood acute lymphoblastic leukemia: results from a single agent window study. Leukemia. 2008 Sep;22(9):1665-79. doi: 10.1038/leu.2008.165. Epub 2008 Jun 26. [PubMed:18580955]
  3. Asparlas Approval History [Link]
  4. NCI: Calaspargase Pegol [Link]
  5. Blood Journal: Randomized Study of Pegaspargase (SS-PEG) and Calaspargase Pegol (SPC-PEG) in Pediatric Patients with Newly Diagnosed Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma: Results of DFCI ALL Consortium Protocol 11-001 [Link]
  6. Medsafe NZ: Erwinaze inj [File]
Calaspargase pegol-mknl
Clinical data
Trade names Asparlas
Synonyms EZN-2285
Legal status
Legal status
Identifiers
CAS Number
DrugBank
UNII
KEGG
ChEMBL

/////////////Calaspargase pegol, Peptide, FDA 2018, EZN-2285, カラスパルガーゼペゴル  , BAX-2303, SC-PEG E. Coli L-asparaginase , SHP-663, orphan drug

CC(C)C[C@@H](C(=O)O)NC(=O)OCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOC.COCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOC(=O)NCCCC[C@@H](C(=O)O)N

Caplacizumab, カプラシズマブ Cablivi is the first therapeutic approved in Europe, for the treatment of a rare blood-clotting disorder


Cablivi is the first therapeutic approved in Europe, for the treatment of a rare blood-clotting disorder

On September 03, 2018, the European Commission has granted marketing authorization for Cablivi™ (caplacizumab) for the treatment of adults experiencing an episode of acquired thrombotic thrombocytopenic purpura (aTTP), a rare blood-clotting disorder. Cablivi is the first therapeutic specifically indicated for the treatment of aTTP   1. Cablivi was designated an ‘orphan medicine’ (a medicine used in rare diseases) on April 30, 2009. The approval of Cablivi in the EU is based on the Phase II TITAN and Phase III HERCULES studies in 220 adult patients with aTTP. The efficacy and safety of caplacizumab in addition to standard-of-care treatment, daily PEX and immunosuppression, were demonstrated in these studies. In the HERCULES study, treatment with caplacizumab in addition to standard-of-care resulted in a significantly shorter time to platelet count response (p<0.01), the study’s primary endpoint; a significant reduction in aTTP-related death, recurrence of aTTP, or at least one major thromboembolic event during study drug treatment (p<0.0001); and a significantly lower number of aTTP recurrences in the overall study period (p<0.001). Importantly, treatment with caplacizumab resulted in a clinically meaningful reduction in the use of PEX and length of stay in the intensive care unit (ICU) and the hospital, compared to the placebo group. Cablivi was developed by Ablynx, a Sanofi company. Sanofi Genzyme, the specialty care global business unit of Sanofi, will work with relevant local authorities to make Cablivi available to patients in need in countries across Europe.

About aTTP aTTP is a life-threatening, autoimmune blood clotting disorder characterized by extensive clot formation in small blood vessels throughout the body, leading to severe thrombocytopenia (very low platelet count), microangiopathic hemolytic anemia (loss of red blood cells through destruction), ischemia (restricted blood supply to parts of the body) and widespread organ damage especially in the brain and heart. About Cablivi Caplacizumab blocks the interaction of ultra-large von Willebrand Factor (vWF) multimers with platelets and, therefore, has an immediate effect on platelet adhesion and the ensuing formation and accumulation of the micro-clots that cause the severe thrombocytopenia, tissue ischemia and organ dysfunction in aTTP   2.

Note – Caplacizumab is a bivalent anti-vWF Nanobody that received Orphan Drug Designation in Europe and the United States in 2009, in Switzerland in 2017 and in Japan in 2018. The U.S. Food and Drug Administration (FDA) has accepted for priority review the Biologics License Application for caplacizumab for treatment of adults experiencing an episode of aTTP. The target action date for the FDA decision is February 6, 2019

1 http://hugin.info/152918/R/2213684/863478.pdf

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/004426/WC500255075.pdf

Image result for Caplacizumab

More………….

EVQLVESGGG LVQPGGSLRL SCAASGRTFS YNPMGWFRQA PGKGRELVAA ISRTGGSTYY
PDSVEGRFTI SRDNAKRMVY LQMNSLRAED TAVYYCAAAG VRAEDGRVRT LPSEYTFWGQ
GTQVTVSSAA AEVQLVESGG GLVQPGGSLR LSCAASGRTF SYNPMGWFRQ APGKGRELVA
AISRTGGSTY YPDSVEGRFT ISRDNAKRMV YLQMNSLRAE DTAVYYCAAA GVRAEDGRVR
TLPSEYTFWG QGTQVTVSS
(disulfide bridge: 22-96, 153-227)

Sequence:

1EVQLVESGGG LVQPGGSLRL SCAASGRTFS YNPMGWFRQA PGKGRELVAA
51ISRTGGSTYY PDSVEGRFTI SRDNAKRMVY LQMNSLRAED TAVYYCAAAG
101VRAEDGRVRT LPSEYTFWGQ GTQVTVSSAA AEVQLVESGG GLVQPGGSLR
151LSCAASGRTF SYNPMGWFRQ APGKGRELVA AISRTGGSTY YPDSVEGRFT
201ISRDNAKRMV YLQMNSLRAE DTAVYYCAAA GVRAEDGRVR TLPSEYTFWG
251QGTQVTVSS

EU 2018/8/31 APPROVED, Cablivi

Treatment of thrombotic thrombocytopenic purpura, thrombosis

Immunoglobulin, anti-(human von Willebrand’s blood-coagulation factor VIII domain A1) (human-Lama glama dimeric heavy chain fragment PMP12A2h1)

Other Names

  • 1: PN: WO2011067160 SEQID: 1 claimed protein
  • 98: PN: WO2006122825 SEQID: 98 claimed protein
  • ALX 0081
  • ALX 0681
  • Caplacizumab
Formula
C1213H1891N357O380S10
CAS
915810-67-2
Mol weight
27875.8075

Caplacizumab (ALX-0081) (INN) is a bivalent VHH designed for the treatment of thrombotic thrombocytopenic purpura and thrombosis.[1][2]

This drug was developed by Ablynx NV.[3] On 31 August 2018 it was approved in the European Union for the “treatment of adults experiencing an episode of acquired thrombotic thrombocytopenic purpura (aTTP), in conjunction with plasma exchange and immunosuppression”.[4]

It is an anti-von Willebrand factor humanized immunoglobulin.[5] It acts by blocking platelet aggregation to reduce organ injury due to ischemia.[5] Results of the phase II TITAN trial have been reported.[5]

PATENTS

WO 2006122825

WO 2009115614

WO 2011067160

WO 2011098518

WO 2011162831

WO 2013013228

WO 2014109927

WO 2016012285

WO 2016138034

WO 2016176089

WO 2017180587

WO 2017186928

WO 2018067987

Image result for Caplacizumab

References

Caplacizumab
Monoclonal antibody
Type Single domain antibody
Source Humanized
Target VWF
Clinical data
Synonyms ALX-0081
ATC code
  • none
Identifiers
CAS Number
ChemSpider
  • none
KEGG
Chemical and physical data
Formula C1213H1891N357O380S10
Molar mass 27.88 kg/mol

/////////////eu 2018, Caplacizumab, nti-vWF Nanobody, Orphan Drug Designation, aTTP, Cablivi, Ablynx, Sanofi , ALX-0081, カプラシズマブ  , PEPTIDE, ALX 0081

Burosumab-twza, ブロスマブ


> Burosumab Heavy Chain Sequence
QVQLVQSGAEVKKPGASVKVSCKASGYTFTNHYMHWVRQAPGQGLEWMGIINPISGSTSN
AQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARDIVDAFDFWGQGTMVTVSSAST
KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY
SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSV
FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY
RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK
NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG
NVFSCSVMHEALHNHYTQKSLSLSPGK
> Burosumab Light Chain Sequence
AIQLTQSPSSLSASVGDRVTITCRASQGISSALVWYQQKPGKAPKLLIYDASSLESGVPS
RFSGSGSGTDFTLTISSLQPEDFATYYCQQFNDYFTFGPGTKVDIKRTVAAPSVFIFPPS
DEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTL
SKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

ALSO

(Heavy chain)
QVQLVQSGAE VKKPGASVKV SCKASGYTFT NHYMHWVRQA PGQGLEWMGI INPISGSTSN
AQKFQGRVTM TRDTSTSTVY MELSSLRSED TAVYYCARDI VDAFDFWGQG TMVTVSSAST
KGPSVFPLAP SSKSTSGGTA ALGCLVKDYF PEPVTVSWNS GALTSGVHTF PAVLQSSGLY
SLSSVVTVPS SSLGTQTYIC NVNHKPSNTK VDKKVEPKSC DKTHTCPPCP APELLGGPSV
FLFPPKPKDT LMISRTPEVT CVVVDVSHED PEVKFNWYVD GVEVHNAKTK PREEQYNSTY
RVVSVLTVLH QDWLNGKEYK CKVSNKALPA PIEKTISKAK GQPREPQVYT LPPSRDELTK
NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS DGSFFLYSKL TVDKSRWQQG
NVFSCSVMHE ALHNHYTQKS LSLSPGK
(Light chain)
AIQLTQSPSS LSASVGDRVT ITCRASQGIS SALVWYQQKP GKAPKLLIYD ASSLESGVPS
RFSGSGSGTD FTLTISSLQP EDFATYYCQQ FNDYFTFGPG TKVDIKRTVA APSVFIFPPS
DEQLKSGTAS VVCLLNNFYP REAKVQWKVD NALQSGNSQE SVTEQDSKDS TYSLSSTLTL
SKADYEKHKV YACEVTHQGL SSPVTKSFNR GEC
(dimer; disulfide bridge:H22-H96, H144-H200, H220-L213, H220-H’226, H229-H’229, H261-H321, H367-H425, H’22-H’96, H’144-H’200, H’220-L’213, H’261-H’321, H’367-H’425, L23-L88, L133-L193, L’23-L’88, L’133-L’193)

Burosumab-twza, KRN 23

ブロスマブ

CAS1610833-03-8

UNII G9WJT6RD29

Protein chemical formulaC6388H9904N1700O2006S46

Protein average weight144100.0 Da

Protein Based Therapies
Monoclonal antibody (mAb)

breakthrough therapy and orphan drug designations

Approval Status:Approved April 2018

Specific Treatments:X-linked hypophosphatemia

Crysvita (burosumab-twza) is a fibroblast growth factor 23 (FGF23) blocking antibody.

This drug is indicated for the treatment of X-linked hypophosphatemia with radiological evidence of bone disease in children of 1 year of age and older and adolescents with growing skeletons [4].

Burosumab (INN, trade name Crysvita) known as KRN23 is a human monoclonal antibody designed for the treatment of X-linked hypophosphatemia.[1][2][3] Burosumab was approved by the FDA for its intended purpose, in patients aged 1 year and older, on 17 April 2018.[4] The FDA approval fell under both the breakthrough therapy and orphan drug designations.[4]

This drug was developed by Ultragenyx and is in a collaborative license agreement with Kyowa Hakko Kirin.[5]

Burosumab (KRN23) is an entirely human monoclonal IgG1 antibody that binds excess fibroblast growth factor 23 (FGF23) and has been successfully tested in clinical trials in children with X-linked hypophosphatemic rickets [1].

The U.S. Food and Drug Administration approved Crysvita (burosumab) in April 2018. This is the first drug approved to treat adults and children ages 1 year and older with X-linked hypophosphatemia (XLH), which is a rare, inherited form of rickets. X-linked hypophosphatemia causes low circulating levels of phosphorus in the blood. It causes impaired bone growth and development in children and adolescents and issues with bone mineralization throughout a patient’s life [3].

XLH is a serious disease which affects about 3,000 children and 12,000 adults in the United States. Most children with XLH suffer from bowed or bent legs, short stature, bone pain and severe dental pain. Some adults with this condition suffer from persistent, unrelenting discomfort and complications, such as joint pain, impaired mobility, tooth abscesses and hearing loss [3]

Crysvita is specifically indicated for the treatment of X-linked hypophosphatemia (XLH) in adult and pediatric patients 1 year of age and older.

Crysvita is supplied as a subcutaneous injection. The recommended starting dose for pediatrics is 0.8 mg/kg of body weight, rounded to the nearest 10 mg, administered every two weeks. The minimum starting dose is 10 mg up to a maximum dose of 90 mg. After initiation of treatment with Crysvita, measure fasting serum phosphorus every 4 weeks for the first 3 months of treatment, and thereafter as appropriate. If serum phosphorus is above the lower limit of the reference range for age and below 5 mg/dL, continue treatment with the same dose. Follow dose adjustment schedule per the drug label. The recommended dose regimen in adults is 1 mg/kg body weight, rounded to the nearest 10 mg up to a maximum dose of 90 mg, administered every four weeks.  After initiation of treatment with Crysvita, assess fasting serum phosphorus on a monthly basis, measured 2 weeks post-dose, for the first 3 months of treatment, and thereafter as appropriate. If serum phosphorus is within the normal range, continue with the same dose. See drug label for specific dose adjustments.

Mechanism of Action

Crysvita (burosumab-twza) is a fibroblast growth factor 23 (FGF23) blocking antibody. X-linked hypophosphatemia is caused by excess fibroblast growth factor 23 (FGF23) which suppresses renal tubular phosphate reabsorption and the renal production of 1,25 dihydroxy vitamin D. Burosumab-twza binds to and inhibits the biological activity of FGF23 restoring renal phosphate reabsorption and increasing the serum concentration of 1,25 dihydroxy vitamin D.

REFERENCES

1 file:///H:/761068Orig1s000ChemR.pdf

REF

  • Kutilek S: Burosumab: A new drug to treat hypophosphatemic rickets. Sudan J Paediatr. 2017;17(2):71-73. doi: 10.24911/SJP.2017.2.11. [PubMed:29545670]
  • Kinoshita Y, Fukumoto S: X-linked hypophosphatemia and FGF23-related hypophosphatemic diseases -Prospect for new treatment. Endocr Rev. 2018 Jan 26. pii: 4825438. doi: 10.1210/er.2017-00220. [PubMed:29381780]
  • FDA approves first therapy for rare inherited form of rickets, x-linked hypophosphatemia [Link]
  • Crysvita Drug Label [Link]
  • Burosumab for a rare bone disease [Link]
  • DRUG: Burosumab [Link]
  • NHS document [Link]
  • Burosumab for XLH [Link]
Burosumab
Monoclonal antibody
Type Whole antibody
Source Human
Target FGF 23
Clinical data
Trade names Crysvita
Synonyms KRN23
ATC code
Identifiers
CAS Number
ChemSpider
  • none
UNII
KEGG
Chemical and physical data
Formula C6388H9904N1700O2006S46
Molar mass 144.1 kDa

References

//////////////Burosumab-twza, Crysvita  FDA 2018, BLA 761068, Protein Based Therapies, Monoclonal antibody, mAb, KRN 23,  breakthrough therapyorphan drug designations, Peptide, ブロスマブ

Efmoroctocog alfa, エフモロクトコグアルファ;


(Heavy chain)
ATRRYYLGAV ELSWDYMQSD LGELPVDARF PPRVPKSFPF NTSVVYKKTL FVEFTDHLFN
IAKPRPPWMG LLGPTIQAEV YDTVVITLKN MASHPVSLHA VGVSYWKASE GAEYDDQTSQ
REKEDDKVFP GGSHTYVWQV LKENGPMASD PLCLTYSYLS HVDLVKDLNS GLIGALLVCR
EGSLAKEKTQ TLHKFILLFA VFDEGKSWHS ETKNSLMQDR DAASARAWPK MHTVNGYVNR
SLPGLIGCHR KSVYWHVIGM GTTPEVHSIF LEGHTFLVRN HRQASLEISP ITFLTAQTLL
MDLGQFLLFC HISSHQHDGM EAYVKVDSCP EEPQLRMKNN EEAEDYDDDL TDSEMDVVRF
DDDNSPSFIQ IRSVAKKHPK TWVHYIAAEE EDWDYAPLVL APDDRSYKSQ YLNNGPQRIG
RKYKKVRFMA YTDETFKTRE AIQHESGILG PLLYGEVGDT LLIIFKNQAS RPYNIYPHGI
TDVRPLYSRR LPKGVKHLKD FPILPGEIFK YKWTVTVEDG PTKSDPRCLT RYYSSFVNME
RDLASGLIGP LLICYKESVD QRGNQIMSDK RNVILFSVFD ENRSWYLTEN IQRFLPNPAG
VQLEDPEFQA SNIMHSINGY VFDSLQLSVC LHEVAYWYIL SIGAQTDFLS VFFSGYTFKH
KMVYEDTLTL FPFSGETVFM SMENPGLWIL GCHNSDFRNR GMTALLKVSS CDKNTGDYYE
DSYEDISAYL LSKNNAIEPR SFSQNPPVLK RHQREITRTT LQSDQEEIDY DDTISVEMKK
EDFDIYDEDE NQSPRSFQKK TRHYFIAAVE RLWDYGMSSS PHVLRNRAQS GSVPQFKKVV
FQEFTDGSFT QPLYRGELNE HLGLLGPYIR AEVEDNIMVT FRNQASRPYS FYSSLISYEE
DQRQGAEPRK NFVKPNETKT YFWKVQHHMA PTKDEFDCKA WAYFSDVDLE KDVHSGLIGP
LLVCHTNTLN PAHGRQVTVQ EFALFFTIFD ETKSWYFTEN MERNCRAPCN IQMEDPTFKE
NYRFHAINGY IMDTLPGLVM AQDQRIRWYL LSMGSNENIH SIHFSGHVFT VRKKEEYKMA
LYNLYPGVFE TVEMLPSKAG IWRVECLIGE HLHAGMSTLF LVYSNKCQTP LGMASGHIRD
FQITASGQYG QWAPKLARLH YSGSINAWST KEPFSWIKVD LLAPMIIHGI KTQGARQKFS
SLYISQFIIM YSLDGKKWQT YRGNSTGTLM VFFGNVDSSG IKHNIFNPPI IARYIRLHPT
HYSIRSTLRM ELMGCDLNSC SMPLGMESKA ISDAQITASS YFTNMFATWS PSKARLHLQG
RSNAWRPQVN NPKEWLQVDF QKTMKVTGVT TQGVKSLLTS MYVKEFLISS SQDGHQWTLF
FQNGKVKVFQ GNQDSFTPVV NSLDPPLLTR YLRIHPQSWV HQIALRMEVL GCEAQDLYDK
THTCPPCPAP ELLGGPSVFL FPPKPKDTLM ISRTPEVTCV VVDVSHEDPE VKFNWYVDGV
EVHNAKTKPR EEQYNSTYRV VSVLTVLHQD WLNGKEYKCK VSNKALPAPI EKTISKAKGQ
PREPQVYTLP PSRDELTKNQ VSLTCLVKGF YPSDIAVEWE SNGQPENNYK TTPPVLDSDG
SFFLYSKLTV DKSRWQQGNV FSCSVMHEAL HNHYTQKSLS LSPG
(Lignt chain)
DKTHTCPPCP APELLGGPSV FLFPPKPKDT LMISRTPEVT CVVVDVSHED PEVKFNWYVD
GVEVHNAKTK PREEQYNSTY RVVSVLTVLH QDWLNGKEYK CKVSNKALPA PIEKTISKAK
GQPREPQVYT LPPSRDELTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS
DGSFFLYSKL TVDKSRWQQG NVFSCSVMHE ALHNHYTQKS LSLSPG
(disulfide bridges: H153-H179, H248-H329, H528-H554, H630-H711, H938-H964, H1005-H1009, H1127-H1275, H1280-H1432, H1444-L6, H1447-L9, H1479-H1539, H1585-H1643, L41-L101, L147-L205)

Efmoroctocog alfa

Protein chemical formulaC9736H14863N2591O2855S78

Protein average weight220000.0 Da (Apparent, B-domain deleted)

Peptide

CAS: 1270012-79-7

エフモロクトコグアルファ;

2015/11/19 ema APPROVED elocta

Image result for Efmoroctocog alfa

Image result for Efmoroctocog alfa

Efmoroctocog alfa is a fully recombinant factor VIII-Fc fusion protein (rFVIIIFc) with an extended half-life compared with conventional factor VIII (FVIII) preparations, including recombinant FVIII (rFVIII) products such as Moroctocog alfa[1]. It is an antihemorrhagic agent used in replacement therapy for patients with haemophilia A (congenital factor VIII deficiency). It is suitable for all age groups. Haemophilia A is a rare bleeding disorder associated with a slow clotting process caused by the deficiency of factor VIII. Patients with this disorder are more susceptible to recurrent bleeding episodes and excessive bleeding following minor traumatic injuries or surgical procedures [1]. Prophylactic treatment may dramatically improve the management of severe haemophilia A in the future by reducing joint bleeding and other hemorrhages that cause chronic pain and disability to patients [12]. Prophylaxis has also shown to reduce the formation of neutralizing anti-FVIII antibodies, or inhibitors [2].

Factor VIII is a blood coagulant factor involved in the intrinsic pathway to form fibrin, or a blood clot. Efmoroctocog alfa is a first commercially available rFVIII-Fc fusion protein (rFVIIIFc) where the conjugated molecule of rFVIII to polyethylene glycol is covalently fused to the dimeric Fc domain of human immunoglobulin G1, a long-lived plasma protein [FDA Label]. The B domain of factor VIII is deleted. In animal models of haemophilia, efmoroctocog alfa demonstrated an approximately two-fold longer t½ than commercially available rFVIII products [1].

Other drug products with similar structure and function to Efmoroctocog alfa include Moroctocog alfa, which is produced by recombinant DNA technology and is identical in sequence to endogenously produced Factor VIII, but does not contain the B-domain, which has no known biological function, and Antihemophilic factor human, which is purified endogenous Factor VIII from human pooled blood and contains both A- and B-subunits.

It is commonly marketed as Elocta or Eloctate for intravenous injection. To date, no confirmed inhibitory autoantibodies were seen in previously treated patients included in clinical studies and treatment-emergent adverse events were generally consistent with those expected in the patient populations being studied [1]. The extended half-life of efmoroctocog alfa provides several clinical benefits for patients, including reduced frequency of injections required and improved adherence to prophylaxis [1].

Haemophilia A is an inherited sex-linked disorder of blood coagulation in which affected males (very rarely females) do not produce functional coagulation FVIII in sufficient quantities to achieve satisfactory haemostasis. The incidence of congenital haemophilia A is approximately 1 in 10,000 births. Disease severity is classified according to the level of FVIII activity (% of normal) as mild (>5% to <40%), moderate (1% to 5%) or severe (<1%). This deficiency in FVIII predisposes patients with haemophilia A to recurrent bleeding episodes in joints, muscles or internal organs, either spontaneously or as a result of accidental or surgical trauma. Without adequate treatment these repeated haemarthroses and haematomas lead to long-term sequelae with severe disability. Other less frequent, but more severe bleeding sites, are the central nervous system, the urinary or gastrointestinal tract, eyes and the retro-peritoneum. Patients with haemophilia A are at high risk of developing major and life-threatening bleeds after surgical procedures, even after minor procedures such as tooth extraction. The development of cryoprecipitate and subsequently FVIII concentrates, obtained by fractionation of human plasma, provided replacement FVIII and greatly improved clinical management and life expectancy of patients with haemophilia A. Current treatment approaches focus on either prophylactic or on demand factor replacement therapy with plasma-derived FVIII or recombinant FVIII products. In the short term, prophylaxis can prevent spontaneous bleeding and in the long term, prophylaxis can prevent bleeding into joints that will eventually lead to debilitating arthropathy. Prophylaxis with FVIII concentrates is currently the preferred treatment regimen for patients with severe haemophilia A, especially in very young patients. The majority of patients receiving prophylaxis are treated 3-times weekly or every other day at a dose of 25–40 international units (IU)/kg (or 15–25 IU/kg in an intermediate dose regimen), although an escalating dose regimen is also used. However, on-demand treatment is still the predominant replacement approach in many countries. The most serious complication in the treatment of haemophilia A is the development of neutralising antibodies (inhibitors) against FVIII, rendering the patient resistant to replacement therapy and thereby increasing the risk of unmanageable bleeding, particularly arthropathy, and disability.

ELOCTA (efmoroctocog alfa) is a recombinant human coagulation factor VIII Fc fusion protein (rFVIIIFc) consisting of B-domain deleted FVIII covalently attached to the Fc domain of human immunoglobulin G1 (IgG1) thus aiming at prolongation of plasma half-life. It has been developed as a long-acting version of recombinant FVIII (rFVIII) for the control and prevention of bleeding episodes, routine prophylaxis, and perioperative management (surgical prophylaxis) in individuals with hemophilia A. ELOCTA is formulated as powder for intravenous administration in a single-use vial. Each single-use vial contains nominally 250, 500, 750, 1000, 1500, 2000, or 3000 International Units (IU) of rFVIIIFc for reconstitution with a solvent (Sterile Water for Injections), which is provided in a pre-filled syringe. In 2013, national scientific advice was sought from the United Kingdom Medicines and Healthcare Products Regulatory Agency (MHRA), Swedish Medicinal Products Agency, and German Paul-Ehrlich-Institute. No substantial deviations from the advices provided could be identified. On 2 April 2014, the Paediatric Committee (PDCO) of the European Medicines Agency adopted a favourable opinion on the modification of an agreed paediatric investigation plan (PIP) (P/0077/2014) and a partially completed compliance procedure was finalised on 16-18 July 2014 (EMEA-C1-001114-PIP01-10-MO2). Completed studies, Study 997HA301 and Study 8HA02PED, and the initiation of Study 8HA01EXT are considered compliant with EMA Decision P/0077/2014.

The active substance of ELOCTA, efmoroctocog alfa, is a recombinant human coagulation factor VIII, Fc fusion protein (rFVIIIFc) comprising B-domain deleted (BDD) human FVIII covalently linked to the Fc domain of human immunoglobulin G1(IgG1). It has been developed as a long-acting version of recombinant FVIII (rFVIII). ELOCTA is formulated as a sterile, non-pyrogenic, preservative-free, lyophilized, white to off-white powder to cake for intravenous administration in a single-use vial. Each single-use vial contains nominally 250, 500, 750, 1000, 1500, 2000, or 3000 International Units (IU) of rFVIIIFc for reconstitution with liquid diluent (Sterile Water for Injection), which is provided in a pre-filled syringe. The finished medicinal product consists of a package containing a rFVIIIFc drug product vial, a pre-filled diluent (SWFI) syringe and medical devices (a plunger rod, a vial adapter (used as a transfer device during reconstitution), an infusion set, alcohol swabs, plasters and gauze pad for intravenous administration).

Structure The active substance of Elocta, efmoroctocog alfa, is a recombinant human coagulation factor VIII, Fc fusion protein (rFVIIIFc) comprised of a single molecule of B-domain deleted human Factor VIII (BDD FVIII) fused to the dimeric Fc region of human IgG1 with no intervening linker sequence.

The rFVIIIFc protein has a molecular weight of approximately 220 kDa. rFVIIIFc is synthesized as 2 polypeptide chains, one chain consisting of BDD FVIII fused to the N-terminal of human IgG1 Fc domain the other chain consisting of the same Fc region alone. The two subunits of rFVIIIFc, FVIIIFc single chain and Fc single chain, are associated through disulfide bonds in the hinge region of Fc as well as through extensive noncovalent interactions between the Fc fragments.

Characterisation rFVIIIFc was extensively characterised by physicochemical methods in accordance with guideline ICH Q6B. The structural characterisation and the physicochemical properties confirmed the expected properties for a recombinant FVIIIFc product. In general, the characterization performed was considered appropriate for this complex fusion molecule. The panel of tests was comprehensive and covered most of its structural and functional attributes. The comparability between representative batches from development and commercial manufacture (including process validation batches) as well as with rFVIIIFc reference materials was demonstrated. The biological activity was analysed by the FVIII one stage clotting assay (activated partial thromboplastin time (aPTT)), the FVIII chromogenic assay and the FcRn binding assay. Additional in vitro functional tests were performed comprising the binding to von Willebrand factor and the generation of Factor Xa. Since it is anticipated that the potency of modified products measured by the one stage clotting assay (aPTT) may be dependent on the choice of the aPTT reagent, the ISTH recommends for all new FVIII products to perform a study including assay variations (different aPTT reagents) for FVIII testing when using the coagulation assay. Respective studies were provided by the Applicant in Module 5 (no significant dependence on the aPTT reagent was observed). REF 3

AUSTRALIA REF 4

Submission details Type of submission: New biological entity Decision: Approved Date of decision: 18 June 2014 Active ingredient: Efmoroctocog alfa (rhu2)3

Product name: Eloctate Sponsor’s name and address: Biogen Idec Australia Pty Ltd Suite 1, Level 5 123 Epping Rd North Ryde, NSW 2113 Dose form: Powder for injection and diluent Strengths: 250 international units (IU), 500 IU, 750 IU, 1000 IU, 1500 IU, 2000 IU and 3000 IU Containers: Type I glass vial (powder) and pre-filled syringe (diluent) Pack size: Single Approved therapeutic use: Eloctate is a long-acting antihaemophilic factor (recombinant) indicated in adults and children ( ≥ 12 years) with haemophilia A (congenital factor VIII deficiency) for: · control and prevention of bleeding episodes · routine prophylaxis to prevent or reduce the frequency of bleeding episodes · perioperative management (surgical prophylaxis) Eloctate does not contain von Willebrand factor, and therefore is not indicated in patients with von Willebrand’s disease. Route of administration: Intravenous (IV) infusion Dosage: Refer to the Product Information (PI; Attachment 1) ARTG numbers: 210521 (250 IU), 210519 (500 IU), 210523 (750 IU), 210525 (1000 IU), 210522 (1500 IU), 210524 (2000 IU), 210520 (3000 IU). 2 recombinant human 3 The ingredient name at the time of submission and registration was Efraloctocog alfa, The name was subsequently changed on 20 February 2015 to harmonise to the International Non-proprietary Name (INN) Efmoroctocog alfa. The AusPAR document has been amended by replacing the previous name efraloctocog alfa with approved INN efmoroctocog alfa.

  1. Frampton JE: Efmoroctocog Alfa: A Review in Haemophilia A. Drugs. 2016 Sep;76(13):1281-1291. doi: 10.1007/s40265-016-0622-z. [PubMed:27487799]
  2. Tiede A: Half-life extended factor VIII for the treatment of hemophilia A. J Thromb Haemost. 2015 Jun;13 Suppl 1:S176-9. doi: 10.1111/jth.12929. [PubMed:26149020]
  3. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/003964/WC500198644.pdf
  4. https://www.tga.gov.au/sites/default/files/auspar-efmoroctocog-alfa-rhu-150317.pdf
  5. http://www.who.int/medicines/publications/druginformation/innlists/RL73_pre.pdf

///////////Efmoroctocog alfa, Peptide, ema 2015

Abaloparatide, абалопаратид , أبالوباراتيد , 巴罗旁肽 ,


Chemical structure for Abaloparatide

Abaloparatide

BA058
BIM-44058
UNII-AVK0I6HY2U

BA058; BIM-44058; CAS  247062-33-5

MW 3960.5896, MF C174 H300 N56 O49

абалопаратид [Russian] [INN]
أبالوباراتيد [Arabic] [INN]
巴罗旁肽 [Chinese] [INN]
str1

NAME………C2.29-methyl(22-L-glutamic acid(F>E),23-L-leucine(F>L),25-L-glutamic acid(H>E),26-L-lysine(H>K),28-L-leucine(I>L),30-L-lysine(E>K),31-L-leucine(I>L))human parathyroid hormone-related protein-(1-34)-proteinamide
L-Alaninamide, L-alanyl-L-valyl-L-seryl-L-alpha-glutamyl-L-histidyl-L-glutaminyl-L-leucyl-L-leucyl-L-histidyl-L-alpha-aspartyl-L-lysylglycyl-L-lysyl-L-seryl-L-isoleucyl-L-glutaminyl-L-alpha-aspartyl-L-leucyl-L-arginyl-L-arginyl-L-arginyl-L-alpha-glutamyl-L-leucyl-L-leucyl-L-alpha-glutamyl-L-lysyl-L-leucyl-L-leucyl-2-methylalanyl-L-lysyl-L-leucyl-L-histidyl-L-threonyl-

L-Alaninamide, L-alanyl-L-valyl-L-seryl-L-α-glutamyl-L-histidyl-L-glutaminyl-L-leucyl-L-leucyl-L-histidyl-L-α-aspartyl-L-lysylglycyl-L-lysyl-L-seryl-L-isoleucyl-L-glutaminyl-L-α-aspartyl-L-leucyl-L-arginyl-L-arginyl-L-arginyl-L-α-glutamyl-L-leucyl-L-leucyl-L-α-glutamyl-L-lysyl-L-leucyl-L-leucyl-2-methylalanyl-L-lysyl-L-leucyl-L-histidyl-L-threonyl-

  1. C2.29-methyl(22-L-glutamic acid(F>E),23-L-leucine(F>L),25-L-glutamic acid(H>E),26-L-lysine(H>K),28-L-leucine(I>L),30-L-lysine(E>K),31-L-leucine(I>L))human parathyroid hormone-related protein-(1-34)-proteinamide

Biologic Depiction

Abaloparatide biologic depiction
IUPAC Condensed

H-Ala-Val-Ser-Glu-His-Gln-Leu-Leu-His-Asp-Lys-Gly-Lys-Ser-Ile-Gln-Asp-Leu-Arg-Arg-Arg-Glu-Leu-Leu-Glu-Lys-Leu-Leu-Aib-Lys-Leu-His-Thr-Ala-NH2

Sequence

AVSEHQLLHDKGKSIQDLRRRELLEKLLXKLHTA

HELM

PEPTIDE1{A.V.S.E.H.Q.L.L.H.D.K.G.K.S.I.Q.D.L.R.R.R.E.L.L.E.K.L.L.[Aib].K.L.H.T.A.[am]}$$$$

IUPAC

(N-(L-alanyl-L-valyl-L-seryl-L-alpha-glutamyl-L-histidyl-L-glutaminyl-L-leucyl-L-leucyl-L-histidyl-L-alpha-aspartyl-L-lysyl-glycyl-L-lysyl-L-seryl-L-isoleucyl-L-glutaminyl-L-alpha-aspartyl-L-leucyl-L-arginyl-L-arginyl-L-arginyl-L-alpha-glutamyl-L-leucyl-L-leucyl-L-alpha-glutamyl-L-lysyl-L-leucyl-L-leucyl)-2-aminoisobutyryl)-L-lysyl-L-leucyl-L-histidyl-L-threonyl-L-alaninamide

Tymlos

FDA 4/28/2017

To treat osteoporosis in postmenopausal women at high risk of fracture or those who have failed other therapies
Drug Trials Snapshot

2D chemical structure of 247062-33-5

Image result for AbaloparatideImage result for Abaloparatide

CLINICAL……….https://clinicaltrials.gov/search/intervention=Abaloparatide%20OR%20BA058%20OR%20BIM-44058

BIM-44058 is a 34 amino acid analog of native human PTHrP currently in phase III clinical trials at Radius Health for the treatment of postmenopausal osteoporosis. Radius is also developing a microneedle transdermal patch using a 3M drug delivery system in phase II clinical trials. The drug candidate was originally developed at Biomeasure (a subsidiary of Ipsen), and was subsequently licensed to Radius and Teijin Pharma.

Abaloparatide (brand name Tymlos; formerly BA058) is a parathyroid hormone-related protein (PTHrP) analog drug used to treat osteoporosis. Like the related drug teriparatide, and unlike bisphosphonates, it is an anabolic (i.e., bone growing) agent.[1] A subcutaneous injection formulation of the drug has completed a Phase III trial for osteoporosis.[2] This single study found a decrease in fractures.[3] In 28 April 2017, it was approved by Food and drug administration (FDA) to treat postmenopausal osteoporosis.

Image result for Abaloparatide

Therapeutics

Medical use

Abaloparatide is indicated to treat postmenopausal women with osteoporosis who are more susceptible to bone fractures.[2]

Dosage

The dose recommended is 80mcg subcutaneous injection once a day, administered in the periumbilical area using a prefilled pen device containing 30 doses.[4]

Warnings and Precautions

Preclinical studies revealed that abaloparatide systemic daily administration leads to a dose- and time-dependent increase in the incidence of osteosarcoma in rodents.[5] However, whether abaloparatide-SC will cause osteosarcoma in humans is unknown. Thus, the use of abaloparatide is not recommended for individuals at increased risk of osteosarcoma. Additionally, its use is not advised for more than 2 years during a patient’s lifetime.[4][6]

Image result for Abaloparatide

Side Effects

The most common side effects reported by more than 2% of clinical trials subjects are hypercalciuria, dizziness, nausea, headache, palpitations, fatigue, upper abdominal pain and vertigo.[4]

Pharmacology

Abaloparatide is 34 amino acid synthetic analog of PTHrP. It has 41% homology to parathyroid hormone (PTH) (1-34) and 76% homology to parathyroid hormone-related protein (PTHrP) (1-34).[7] It works as an anabolic agent for the bone, through selective activation of the parathyroid hormone 1 receptor (PTH1R), a G protein-coupled receptor (GPCR) expressed in the osteoblasts and osteocytes. Abaloparatide preferentially binds the RG conformational state of the PTH1R, which in turn elicits a transient downstream cyclic AMP signaling response towards to a more anabolic signaling pathway.[8][9]

History

Preclinical studies

Abaloropatide was previously known as BA058 and BIM-44058 while under development. The anabolic effects of abaloparatide on bone were demonstrated in two preclinical studies conducted in ovarectomized rats. Both studies showed increased cortical and trabecular bone volume and density, and trabecular microarchitecture improvement in vertebral and nonvertebral bones after short-term[10] and long-term[11] daily subcutaneous injection of abaloparatide compared to controls. Recent studies indicated a dose-dependent increased in bone mass and strength in long-term abalorapatide treatment.[12] However, it was also indicated that prolonged abalorapatide-SC treatment leads to increased incidence of osteosarcoma.[5] To date, there is no yet evidence for increased risk of bone tumors due to prolonged abalorapatide systemic administration in humans. Based on this preclinical data, the FDA does not advised the use of abaloparatide-SC for more than 2 years, or in patients with history of Paget disease and/or other conditions that exacerbates the risk of developing osteosarcoma.[4]

Clinical Trials

Phase II trials were initiated in 2008. A 24-week randomized trial was conducted in postmenopausal women with osteoporosis (n=222) assessing bone mass density (BMD) changes as the primary endpoint.[13] Significant BMD increase at doses of 40 and 80 mcg were found in the lumbar spine, femur and hips of abaloparatide-treated participants compared to placebo. Additionally, abaloparatide showed superior anabolic effects on the hips compared to teriparatide.[14]

In the phase III (2011-2014) Abaloparatide Comparator Trial in Vertebral Endpoints (ACTIVE) trial, a 18-months randomized, multicenter, double-blinded, placebo-controlled study evaluated the long-term efficacy of abaloparatide compared to placebo and teriparatide in 2,463 postmenopausal women (± 69 years old).[2] Women who received daily injections of abaloparatide experienced substantial reduction in the incidence of fractures compared to placebo. Additionally, greater BMD increase at 6, 12 and 18 months in spinal, hips and femoral bones was observed in abaloparatide compared to placebo and teriparatide-treated subjects.[3]

Participants who completed 18 months of abaloparatide or placebo in the ACTIVE study were invited to participate in an extended open-labeled study – ACTIVExtend study (2012-2016).[15] Subjects (n=1139) received additional 2 years of 70 mg of alendronate, Vitamin D (400 to 800 IU), and calcium (500–1000 mg) supplementation daily. Combined abaloparatide and alendronate therapy reduced significantly the incidence of vertebral and nonvertebral fractures.[16]

A clinical trial assessing the effectiveness of abaloparatide in altering spinal bone mineral density (BMD) in male subjects is expected to start in the first quarter of 2018. If successful, Radius Health aims to submit a sNDA to expand the use of abaloparatide-SC to treat men with osteoporosis.[17]

In addition to the injectable form of abaloparatide, a transdermal patch is also in development.[1]

Commercialization

As previously noted, abaloparatide-SC is manufactured by Radius Health, Inc. (Nasdaq: RDUS), a biomedical company based in Waltham, Massachusetts. This company is focused on the development of new therapeutics for osteoporosis, cancer and endocrine diseases. Abaloparatide is the only drug currently marketed by Radius Health. RDUS reported that sales for abaloparatide were $3.5million for the third quarter of 2017.[17] The company announced a net loss of $57.8 million, or $1.31 per share for the third quarter of 2017, compared to $19.2 million for the same quarter of 2016.[18] The net loss most likely reflects the substantial expenses associated with the preparation and launching of abaloparatide into the US market in May 2017.

In July 2017, Radius Health licensed rights to Teijin Limited for abaloparatide-SC manufacture and commercialization in Japan. Teijin is developing abaloparatide-SC under agreement with Ipsen Pharma S.A.S., and is conducting a phase III clinical trial in Japanese patients with osteoporosis.[19]

Regulatory Information

Radius Health filed a Marketing Authorization Application (MAA) in November 2015,[20] which was validated in December, 2015, and still under regulatory assessment by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA). As in July 2017, the CHMP issued a second Day-180 List of Outstanding Issues, which Radius is addressing with the CHMP.[17]

In February 2016 a NDA was filed to the FDA, Radius NDA for abaloparatide-SC was accepted in May, 2016.[21] A Prescription Drug User Fee Act (PDUFA) date was initially granted in March 30, 2016, but then extended to June 30, 2017.[22] As previously stated, abaloparatide injection was approved for use in postmenopausal osteoporosis on April 28, 2017.[6]

Intellectual Property

Radius Health currently holds three patents on abaloparatide-SC, with expiration dates from 2027-2028.[23] The patents relate to the drug composition (US 8148333), and the drug delivery methods (US 7803770 B2 and US 8748382-B2).

As previously mentioned, Teijin Limited was granted use of Radius Health intellectual property in July 2017, for the development, manufacture and commercialization of abaloparatide-sc in Japan.

PATENT

http://www.google.com/patents/EP2206725A1?cl=en

  1. A peptide of the formula:

    [Glu22, 25, Leu23, 2831, Lys26, Aib29, Nle30]hPTHrP(1-34)NH2;
    [Glu22, 25, Leu23, 28, 3031, Lys26, Aib29]hPTHrP(1-34)NH2; [Glu22, 25,29, Leu23, 28, 30, 31, Lys26]hpTHrP(1-34)NH2; [Glu22, 25, 29, Leu23, 28, 31, Lys26, Nle30]hPTHrP(1-34)NH2; [Ser1, Ile5, Met8, Asn10, Leu11, 23, 28, 31, His14, Cha15, Glu22, 25, Lys26, 30, Aib29]hPTHrP (1-34)NH2; [Cha22, Leu23, 28, 31, Glu25, 29, Lys26, Nle30]hPTHrP(1-34)NH2; [Cha7, 1115]hPTHrP(1-34)NH2; [Cha7, 8, 15]hPTHrP(1-34)NH2; [Glu22, Leu23, 28, Aib25, 29, Lys26]hpTHrP(1-34)NH2; [Aib29]hPTHrP(1-34)NH2; [Glu22, 25, Leu23, 28, 31, Lys26, Aib29, 30]hPTHrP(1-34)NH2; [Glu22, 25, Leu23, 28, 31, Lys26, Aib29]hPTHrP(1-34)NH2; [Glu22, 25, Leu23, 28, 31, Aib26, 29, Lys30] hPTHrP(1-34)NH2; or [Leu27, Aib29]hPTH(1-34)NH2; or a pharmaceutically acceptable salt thereof.

PATENT

SEE……http://www.google.com.ar/patents/US8148333?cl=en

PATENT

SEE…………http://www.google.im/patents/US20090227498?cl=pt

EP5026436A Title not available
US3773919 Oct 8, 1970 Nov 20, 1973 Du Pont Polylactide-drug mixtures
US4767628 Jun 29, 1987 Aug 30, 1988 Imperial Chemical Industries Plc Polylactone and acid stable polypeptide
WO1994001460A1* Jul 13, 1993 Jan 20, 1994 Syntex Inc Analogs of pth and pthrp, their synthesis and use for the treatment of osteoporosis
WO1994015587A2 Jan 5, 1994 Jul 21, 1994 Steven A Jackson Ionic molecular conjugates of biodegradable polyesters and bioactive polypeptides
WO1997002834A1* Jul 3, 1996 Jan 30, 1997 Biomeasure Inc Analogs of parathyroid hormone
WO1997002834A1* 3 Jul 1996 30 Jan 1997 Biomeasure Inc Analogs of parathyroid hormone
WO2008063279A2* 3 Oct 2007 29 May 2008 Radius Health Inc A stable composition comprising a bone anabolic protein, namely a pthrp analogue, and uses thereof
US5695955 * 23 May 1995 9 Dec 1997 Syntex (U.S.A.) Inc. Gene expressing a nucleotide sequence encoding a polypeptide for treating bone disorder
US20030166836 * 6 Nov 2002 4 Sep 2003 Societe De Conseils De Recherches Et D’application Scientefiques, S.A.S., A France Corporation Analogs of parathyroid hormone
US20050282749 * 14 Jan 2005 22 Dec 2005 Henriksen Dennis B Glucagon-like peptide-1 (GLP-1); immunotherapy; for treatment of obesity
Tymlos abaloparatide 4/28/2017 To treat osteoporosis in postmenopausal women at high risk of fracture or those who have failed other therapies
Drug Trials Snapshot
Abaloparatide
Clinical data
Trade names Tymlos
Synonyms BA058, BIM-44058
Routes of
administration
Subcutaneous injection
ATC code
  • none
Legal status
Legal status
  • Investigational
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
Formula C174H299N56O49
Molar mass 3,959.65 g·mol−1
3D model (JSmol)

/////////FDA 2017, Abaloparatide, TYMLOS, RADIUS HEALTH, PEPTIDE, BA058, BIM 44058; 247062-33-5, абалопаратид أبالوباراتيد 巴罗旁肽 

CCC(C)C(C(=O)NC(CCC(=O)N)C(=O)NC(CC(=O)O)C(=O)NC(CC(C)C)C(=O)NC(CCCNC(=N)N)C(=O)NC(CCCNC(=N)N)C(=O)NC(CCCNC(=N)N)C(=O)NC(CCC(=O)O)C(=O)NC(CC(C)C)C(=O)NC(CC(C)C)C(=O)NC(CCC(=O)O)C(=O)NC(CCCCN)C(=O)NC(CC(C)C)C(=O)NC(CC(C)C)C(=O)NC(C)(C)C(=O)NC(CCCCN)C(=O)NC(CC(C)C)C(=O)NC(CC1=CN=CN1)C(=O)NC(C(C)O)C(=O)NC(C)C(=O)N)NC(=O)C(CO)NC(=O)C(CCCCN)NC(=O)CNC(=O)C(CCCCN)NC(=O)C(CC(=O)O)NC(=O)C(CC2=CN=CN2)NC(=O)C(CC(C)C)NC(=O)C(CC(C)C)NC(=O)C(CCC(=O)N)NC(=O)C(CC3=CN=CN3)NC(=O)C(CCC(=O)O)NC(=O)C(CO)NC(=O)C(C(C)C)NC(=O)C(C)N

ELAMIPRETIDE


Elamipretide.pngimg

Elamipretide

Elamipretide biologic depiction

H-D-Arg-Tyr(2,6-diMe)-Lys-Phe-NH2

D-arginyl-2,6-dimethyl-L-tyrosyl-L-lysyl-L-phenylalaninamide

(2S)-6-amino-2-[[(2S)-2-[[(2R)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]-3-(4-hydroxy-2,6-dimethylphenyl)propanoyl]amino]-N-[(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]hexanamide

CAS 736992-21-5

Chemical Formula: C32H49N9O5

Molecular Weight: 639.8

  • A free radical scavenger and antioxidant that localizes in the inner mitochondrial membrane.
  • Mitochondrial Protective Agent to Improve Cell Viability
  1. Elamipretide
  2. bendavia
  3. UNII-87GWG91S09
  4. 736992-21-5
  5. MTP 131
  6. RX 31
  7. SS 31
  8. 87GWG91S09
  9. L-Phenylalaninamide, D-arginyl-2,6-dimethyl-L-tyrosyl-L-lysyl-
  10. SS-31 peptide
  11. Arg-Dmt-Lys-Phe-NH2
  12. D-Arg-Dmt-Lys-Phe-NH2
  13. SS31 peptide
  14. Elamipretide [USAN:INN]
  15. MTP-131
  16. Elamipretide (USAN/INN)
  17. arginyl-2,’6′-dimethyltyrosyl-lysyl-phenylalaninamide
  18. CHEMBL3833370
  19. SCHEMBL15028020
  20. CTK2H1007

Elamipretide is a cardiolipin peroxidase inhibitor and mitochondria-targeting peptide, Improves Left Ventricular and Mitochondrial Function. In vitro: Elamipretide significantly increases enzymatic activities of both complexes to near normal levels.

Background Information

Elamipretide is a cardiolipin peroxidase inhibitor and mitochondria-targeting peptide, Improves Left Ventricular and Mitochondrial Function. In vitro: Elamipretide significantly increases enzymatic activities of both complexes to near normal levels. long-term therapy with elamipretide reduces ROS formation, attenuated mPTP openings, and significantly decreases the levels of cytosolic cytochrome c and active caspase-3, thus suppressing a major signaling pathway for apoptosis. Elamipretide represents a new class of compounds that can improve the availability of energy to failing heart and reduce the burden of tissue injury caused by excessive ROS production. [1] In vivo: Fourteen dogs with microembolization-induced HF are randomized to 3 months monotherapy with subcutaneous injections of elamipretide (0.5 mg/kg once daily. Elamipretide has been shown to enhance ATP synthesis in multiple organs, including heart, kidney, neurons, and skeletal muscle. [1] ……by MedChemexpress Co., Ltd.

Elamipretide (also known as SS-31 and Bendavia)[1][2] is a small mitochondrially-targeted tetrapeptide (D-Arg-dimethylTyr-Lys-Phe-NH2) that appears to reduce the production of toxic reactive oxygen species and stabilize cardiolipin.[3]

Stealth Peptides, a privately held company, was founded in 2006 to develop intellectual property licensed from several universities including elamipretide; it subsequently changed its name to Stealth BioTherapeutics.[4][5]

Acute coronary syndrome; Age related macular degeneration; Cardiac failure; Corneal dystrophy; Diabetic macular edema; Lebers hereditary optic atrophy

  • Originator Stealth Peptides
  • Developer Stealth BioTherapeutics
  • Class Eye disorder therapies; Ischaemic heart disorder therapies; Oligopeptides; Peptides; Small molecules
  • Mechanism of Action Free radical scavengers; Mitochondrial permeability transition pore inhibitors
  • Phase II/III Barth syndrome
    • Phase II Acute kidney injury; Corneal disorders; Heart failure; Leber’s hereditary optic atrophy; Mitochondrial disorders; Reperfusion injury
    • Phase I/II Diabetic macular oedema; Dry age-related macular degeneration; Mitochondrial myopathies
    • Phase I Age-related macular degeneration
    • No development reported Chronic heart failure; Diabetes mellitus; Eye disorders; Neurodegenerative disorders

    Most Recent Events

    • 29 Jun 2017 Initial efficacy and adverse events data from phase II MMPOWER-2 trial in Mitochondrial-myopathies released by Stealth
    • 02 Jun 2017 Stealth BioTherapeutics completes a phase II trial in Heart failure in Germany and Serbia (SC) (NCT02814097)
    • 01 May 2017 Phase-II/III clinical trials in Barth syndrome (In children, In adolescents, In adults, In the elderly) in USA (SC) (NCT03098797)

Novel crystalline salt (eg hydrochloride, mesylate and tosylate salts) forms of D-Arg-Dmt-Lys-Phe-NH2 (referred to as MTP-131 or elamipretide ) and composition comprising them are claimed. See WO2016190852 , claiming therapeutic compositions including chromanyl compounds, variants and analogues and uses thereof. Stealth BioTherapeutics (formerly known as Stealth Peptides) is developing elamipretide, which targets mitochondria, for the potential iv/sc treatment of cardiac reperfusion injury, acute coronary syndrome, acute kidney injury, mitochondrial myopathy, skeletal muscle disorders and congestive heart failure.

Also, the company is developing an oral formulation of elamipretide , which targets mitochondria and reduces the production of excess reactive oxygen species, for treating chronic heart failure. In January 2015, a phase II trial was ongoing . In July 2016, a phase II trial was initiated in Latvia, Spain and Hungary .

Further, the company is developing an ophthalmic formulation of elamipretide , a mitochondria targeting peptide, for treating ocular diseases including diabetic macular edema, age-related macular degeneration and fuchs’ corneal endothelial dystrophy and Leber’s hereditary optic neuropathy.

In April 2016, a phase II trial was initiated for LHON . Family members of the product case of elamipretide ( WO2007035640 ) hold protection in the EU until 2026 and expires in the US in 2027 with US154 extension.

Acute coronary syndrome; Age related macular degeneration; Cardiac failure; Corneal dystrophy; Diabetic macular edema; Lebers hereditary optic atrophy

SYNTHESIS

NEXT………………………

PATENT 2

ELAMIPRETIDE BY STEALTH

WO-2017156403

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017156403&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription


; MTP-131; D-Arg-Dmt-Lys-Phe-Nth). Compound

1 has been shown to affect the mitochondrial disease process by helping to protect organs from oxidative damage caused by excess ROS production and to restore normal ATP production.

PATENT

US 20110082084

WO 2011091357

WO 2012129427

WO 2013059071

WO 2013126775

US 20140378396

US 20140093897

WO 2015134096

WO 2015100376

WO 2015060462

US 20150010588

PATENNT

WO 2015197723

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015197723

PROCESS FOR PREPARING

D-ARGINYL-2,6-DIMETHYL-L-TYROSYL-L-LYSYL-L-PHENYLALANINAMIDE

TECHNICAL FIELD

The invention relates to a process for solution-phase synthesis of D- Arginyl-2,6-dimethyl-L-tyrosyl-L-lysyl-L-phenylalaninamide (abbreviated H-D-Arg-(2,6-Dimethyl)Tyr-L-Lys-L-Phe-NH2, development code SS-31 , MTP-131 , X-31) of Formula (I), an active ingredient developed by Stealth BioTherapeutics under the investigational drug brand names Bendavia® and Ocuvia®, for both common and rare diseases including a mitochondrial targeted therapy for ischemia reperfusion injury.

Formula (I)

BACKGROUND

The product belongs to the class of so-called “Szeto-Schiller peptides”. Szeto-Sciller peptides or “SS peptides” are small, aromatic-cationic, water soluble, highly polar peptides, such as disclosed in US 6703483 and US 7576061 , which can readily penetrate cell membranes. The aromatic-cationic peptides include a minimum of two amino acids, and preferably include a minimum of four amino acids, covalently joined by peptide bonds. The maximum number of amino acids is about twenty amino acids covalently joined by peptide bonds. As described by EP 2012/2436390, optimally, the number of amino acids present in the SS peptides is four.

Bendavia® is being tested for the treatment of ischemia reperfusion injury in patients with acute myocardial infarction (AMI), for the treatment of acute kidney injury (AKI) and renal microvascular dysfunction in hypertension, for the treatment of skeletal muscle dysfunction, for the treatment of mitochondrial myopathy and for the treatment of chronic heart failure. Trials are ongoing to assess the Ocuvia’s potential to treat Leber’s Hereditary Optic Neuropathy (LHON) a devastating inherited disease that causes sudden blindness, often in young adults.

Mitochondria are the cell’s powerhouse, responsible for more than 90% of the energy our bodies need to sustain life and support growth. The energetics from mitochondria maintains healthy physiology and prevents disease. In many common and rare diseases, dysfunctional mitochondria are a key component of disease progression.

D-Arginyl-2,6-dimethyl-L-tyrosyl-L-lysyl-L-phenylalaninamide is a cell-permeable and mitochondria-targeted peptide that showed antioxidant activity and was concentrated in the inner mitochondrial membrane. Compound (< 1 nM) significantly reduced intracellular reactive oxygen species, increased mitochondrial potential and prevented tBHP-induced apoptosis in both N2A and SH-SY5Y neuronal cell lines. In rats, intraperitoneal treatment (1 and 3 mg/kg) 1 day prior to unilateral ureteral obstruction and every day thereafter for 14 days significantly decreased tubular damage, macrophage infiltration and interstitial fibrosis. Compound (3 mg/kg i.p. qd for 2 weeks) also prevented apoptosis and insulin reduction in mouse pancreatic islets caused by streptozotocin.

Further studies performed in a G93A mouse model of amyotrophic lateral sclerosis (ALS) demonstrated that the compound (5 mg/kg/day i.p. starting at 30 days of age) led to a significant delay in disease onset.

Potentially useful for the treatment of ALS and may be beneficial in the treatment of aging and diseases associated with oxidative stress.

In the last few years the peptide H-D-Arg-(2,6-Dimethyl)Tyr-L-Lys-L-Phe-NH2, shown in Fig 1 , and its therapeutic activity have been disclosed and

claimed by in several patent applications.

EP 2436390, US 201 10245182 and US 201 10245183 claim topical anesthetic compositions for application to the skin for pain management or anti-skin aging agents, respectively, comprising Szeto-Schiller peptides; SS-31 is specifically claimed as active ingredient. Sequence of solid-phase synthesis is indicated as the preferred preparation process.

US 7718620 claims a process of treating or preventing ischemia-reperfusion injury of the kidney in a mammal by administrating an effective amount of an aromatic-cationic peptide. SS-31 is specifically claimed as active ingredient.

WO2005/001023 discloses a generical process and carrier complexes for delivering molecules to cells comprising a molecule and an aromatic cationic peptide of type D-Arg-Dmt-Lys-Phe-NH2. The tetrapeptide SS-31 is

specifically claimed as product useful for the process at claim 18.

WO2012/1741 17 and WO2014/210056 claim therapeutic compositions based on SS peptides and the aromatic-cationic peptide D-Arg-Dmt-Lys-Phe-NH2 as active agent.

WO 2013/086020, WO 2004/070054 and WO 2005/072295 provide processes for preventing mithochondrial permeability transition and reducing oxidative damage in a mammal, a removed organ, or a cell in need thereof and specifically claims the process wherein the peptide does not have mu-opioid receptor agonist activity, i.e., D-Arg-Dmt-Lys-Phe-NH2.

WO 2009/108695 discloses a process for protecting a kidney from renal injury which may be associated with decreased or blocked blood flow in the subject’s kidney or exposure to a nephrotoxic agent, such as a radiocontrast dye. The processes include administering to the subject an effective amount of an aromatic-cationic peptide to a subject in need thereof and one of the selected peptide is D-Arg-Dmt-Lys-Phe-NH2.

US 6703483 discloses a detailed procedure for the preparation of novel analogs of DALDA [H-Tyr-D-Arg-Phe-Lys-NH2], namely H-Dmt-D-Arg-Phe-Lys-NH2 using the solid-phase techniques and /?-methylbenzhydrylamine

resin and protocols that have been extensively used by inventor’s laboratory.

Most prior art processes for preparing the compound typically comprise conventionally performed peptide solid-phase synthesis with further purification by chromatography in order to obtain the requested purity for therapeutic use.

It is well known that solid-phase synthesis followed by chromatographic purification is time consuming, very expensive and very difficult to be scaled up on industrial scale, so the need of developing a process for large scale production is obvious. The compound is isolated as organic acid salt, as acetate or trifluoro acetate.

eddy et al., Adv. Exp. Med. Biol, 2009, 61 1 , 473 generally describes the liquid-phase synthesis of antioxidant peptides of Figure 1 and similar others (SS-02, SS-20), involving routinely used side chain protecting groups for amino acid building blocks. The guanidine group was protected with NO2 and the ε-ΝΗ2 of Lys was protected by Cbz or 2-Cl-Cbz. These peptides were

synthesized using Boc/Cbz chemistry and BOP reagent coupling. Starting with the C-terminal Lys residue protected as H-Lys(2-Cl-Cbz)-NH2, (prepared

from the commercially available Boc-Lys(2-Cl-Cbz)-OH in two steps by amidation with NH4HCO3 in the presence of DCC/HOBt following a literature procedure [Ueyama et all, Biopolymers, 1992, 32, 1535, PubMed: 1457730], followed by exposure to TFA). Selective removal of the 2-Cl-Cbz in the

presence of the NO2 group was accomplished using catalytic transfer hydrogenolysis (CTH) [Gowda et al., Lett. Pept. Sci., 2002, 9, 153].

A stepwise procedure by standard solution peptide synthesis for preparation of potent μ agonist [DmtJDALDA and its conversion into a potent δ antagonist H-Dmt-Tic-Phe-Lys(Z)-OH by substitution of D-Arg with Tic to enhance the δ opioid agonist activity is described by Balboni et al., J. Med.

Chem., 2005, 48, 5608. A general synthetic procedure for a similar tetrapeptide ([Dmt-D-Arg-Phe-Lys-NH2 is described by Ballet et al., J. Med.

Chem. 2011, 54, 2467.

Similar DALDA analog tetrapeptides were prepared by the manual solid-phase technique using Boc protection for the a-amino group and DIC/HOBt or HBTU/DIEA as coupling agent [Berezowska et al., J. Med. Chem., 2009, 52, 6941 ; Olma et al., Acta Biochim. Polonica, 2001, 48, 4, 1 121 ; Schiller at al., Eur. J. Med. Chem., 2000, 35, 895].

Despite the high overall yield in the solid-phase approach, it has several drawbacks for the scale-up process such as:

a. the application of the highly toxic and corrosive hydrogen fluoride for cleavage of the peptide from the resin,

b. low loading (0.3-0.35 mmol/g of resin) proved necessary for successful end-step, and

c. use of excess amounts of reagents (3-fold of DIC, 2.4-fold of HOBt, etc.) on each step [ yakhovsky et al., Beilstein J. Org. Chem., 2008, 4(39), 1 , doi: 10.376/bjoc.4.39]

SUMMARY

The invention relates to a more efficient process avoiding either solid-phase synthesis or chromatographic purification, more suitable for large scale production. The process of the invention is described in Scheme A.

The following abbreviations are used:

Dmt = 2,6-dimethyl tyrosine; Z= benzyloxycarbonyl; MeSO3H = methane sulphonic acid; Boc = Tert-butyloxycarbonyl; NMM = N-methyl morpholine; TBTU= N,N,N’,N’-Tetramethyl-O-(benzotriazol- l-yl)uronium tetrafluoroborate; DMF = dimethyl formamide; TFA = trifluoroacetic acid

Scheme A shows the process for the solution phase synthesis of peptide

1 for assembly of the tetrapeptide backbone using O-Benzyl (Bzl) group and benzyloxycarbonyl (Z) group respectively, as the temporary protection for amino acids’ N-termini (Scheme Figure 2), followed by a final catalytic hydrogenolysis. The final product is isolated as organic acid salt, for example, acetic acid salt.

H-Phe-NH 2 + Boc-Lys(Z)-OH

Boc-Lys(Z)-Phe-NH 2

(IV)

(V) I MeS03H/CH2CI2

Boc-DMTyr(Bzl)-OH + MeS03H.H-Lys(Z)-Phe-NH 2

(

Boc-DMTyr(Bzl)-Lys(Z)-Phe-NH 2

(VIII)

I MeS03H/CH2CI2

Z-D-Arg-ONa + H-DMTyr(Bzl)-Lys(Z)-Phe-NH 2.MeS03H

(X) (IX)

TBTU/NMM/DMF

Z-D-Arg-DMTyr(Bzl)-Lys(Z)-Phe-NH

(XI)

I H2, Pd/C

X ACOH

H-D-Arg-DMTyr-Lys-Phe-NH

(I)

Scheme A

This process is a notable improvement with respect to the prior art and its advantages can be summarized as follows:

• The synthesis is performed in liquid phase allowing the scale up on industrial scale without need of special equipment; · The selection of the protecting group in the building blocks allows a straightforward synthesis with very simple deprotection at each step and minimize the formation of undesired by-product;

• Each intermediate can be crystallized allowing removal of impurities which are not transferred to the following step;

· The purity of each intermediate is very high and usually close to

99%.

EXAMPLES

Example 1: Preparation of Boc-Lys(Z)-Phe-NH2

Charge 200 mL of DMF, 44 g of Boc-Lys(Z)-OH and 15.6 g of H-Phe-NH2 in a flask. Stir the mixture at room temperature for 10 min. Add 19.2 g of

N-methylmorpholine and 32.1 g of TBTU successively at room temperature. Stir the mixture at room temperature for 1 h. Add 500 mL of water into the reaction mixture to precipitate the product at room temperature. Filter the mixture to isolate the solid product and wash the filter cake with water.

Transfer the filter cake into a flask containing 360 mL of ethyl acetate and heat the mixture at 50°C till all the solid is dissolved. Separate the organic phase of product and discard the small aqueous phase. Concentrate the organic phase at 40~45°C and under vacuum to remove the solvent till lots of solid is formed. Filter the residue to isolate the solid product. Transfer the filter cake into a flask containing 2000 mL of MTBE and heat the mixture at refluxing for 20 min. Then, cool down the mixture to room temperature. Filter the mixture to isolate the solid product. Dry the filter cake at 30 °C and under vacuum to give 35 g of solid product.

Example 2: Preparation of H-Lys(Z)-Phe-NH2.MeSC>3H

Charge 26.3 g of Boc-Lys(Z)-Phe-NH2, 200 mL of methylene chloride

and 9.6 g of methanesulfonic acid. Stir the mixture at 15-20 °C for 18 h. Add 100 mL of MTBE into the mixture and stir at 15-20 °C for 1 h. Filter the mixture to isolate the solid product. Dry the wet cake in air at room temperature to give 26.4 g of white solid product.

Example 3: Preparation of Boc-DMeTyr(Bzl)-Lys(Z)-Phe-NH2

Charge 8.4 g of Boc-DMeTyr(Bzl)-OH, 1 1 g of H-Lys(Z)-Phe-NH2.MeSO3H, 7.4 g of TBTU and 80 mL of THF in a flask. Stir the mixture

at room temperature for 15 min, and then cool down to 10°C. Add 6.36 g of N-methylmorpholine and stir the mixture at 20-25°C for 3 h. Add the reaction mixture into a flask containing 240 mL of water. Add 32 mL of methylene chloride into the mixture obtained in the previous operation of. Stir the resultant mixture at room temperature for 20 min. Filter the mixture to isolate the solid product and wash the filter cake with acetone (300 mL X 2). Dry the filter cake in air at room temperature to give 14.3 g of white solid product.

Example 4: Preparation of H-DMeTyr(Bzl)-Lys(Z)-Phe-NH2.MeS03H

Charge 14 g of Boc-BMeTyr(Bzl)-Lys(Z)-Phe-NH2, 280 mL of methylene chloride and 3.3 g of methanesulfonic acid in a flask. Stir the mixture at 18 ~ 22 °C for 10 h. Add 560 mL of heptanes into the mixture and stir the mixture at room temperature for 30 min. Filter the mixture to isolate the solid product. Dry the wet cake in air at room temperature to give 14 g of white solid product.

Example 5: Preparation of Z-D-Arg-DMeTyr(Bzl)-Lys(Z)-Phe-NH2

Charge 6.34 g of Z-D-Arg-ONa, 100 mL of DMF and 2.0 g of methanesulfonic acid in a flask. Stir the mixture at room temperature till a clear solution was formed. Add 14 g of H-DMeTyr(Bzl)-Lys(Z)-Phe-NH2.MeSO3H and cool down the mixture to 10°C. Add 6.15 g of TBTU and

9.67 g of N-methylmorpholine successively. Stir the mixture at room temperature for 4 h. Add aqueous solution of LiOH prepared by dissolving 2.9 g of LiOH.L O in 8 mL of water. Stir the mixture for 30 min. Add the resultant mixture slowly into a flask containing 420 mL of water under stirring. Add 56 mL of methylene chloride into the mixture. Filter the mixture to isolate the solid product. Transfer the filter cake into a flask containing 150 mL of acetic acid, and heat the mixture at 35-40 °C till most of the solid was dissolved. Add 450 mL of MTBE into the mixture and cool down the mixture under stirring to room temperature. Filter the mixture to isolate the solid product. Dry the filter cake in air at room temperature to give 17.3 g of the white solid product.

Example 6 Preparation of H-D-Arg-DMeTyr-Lys-Phe-NH2.3AcOH

Charge 2.0 g of Z-D-Arg-DMeTyr(Bzl)-Lys(Z)-Phe-NH2, 20 mL of acetic acid and 5% Pd/C catalyst (which is obtained by washing 5.0 g of 5% Pd/C containing 60% of water with 30 mL of acetic acid) in a flask. Change the atmosphere of the flask with hydrogen. Stir the mixture at room temperature and pressure of 1 atm of hydrogen for 2 h. Filter the mixture to remove the Pd/C catalyst and wash the filter cake with 10 mL of acetic acid. Combine the filtrate and washing solution and concentrate the solution at 20°C and under vacuum to remove most the solvent. Add 100 mL of acetonitrile into the residue and stir the mixture at room temperature for 20 min. Filter the mixture to isolate the solid product. Dry the filter cake at room temperature and under vacuum to give 0.7 g of the white product.

PATENT

WO 2016001042

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016001042&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

References

  1. Jump up^ “Recommended INN List 75” (PDF). WHO Drug Information30 (1): 111. 2016.
  2. Jump up^ “Elamipretide”. AdisInsight. Retrieved 24 April 2017.
  3. Jump up^ Kloner, RA; Shi, J; Dai, W (February 2015). “New therapies for reducing post-myocardial left ventricular remodeling.”Annals of translational medicine3 (2): 20. PMC 4322169Freely accessiblePMID 25738140.
  4. Jump up^ Valigra, Lori (April 9, 2012). “Stealth Peptides sees positive results from Bendavia”Boston Business Journal.
  5. Jump up^ Dolgin, Elie (11 February 2016). “New drugs offer hope for mitochondrial disease”STAT.
Patent ID

Patent Title

Submitted Date

Granted Date

US2017152289 PROCESS FOR THE PRODUCTION OF D-ARGINYL-2, 6-DIMETHYL-L-TYROSYL-L-LYSYL-L-PHENYLALANINAMIDE 2015-06-24
Patent ID

Patent Title

Submitted Date

Granted Date

US2014294796 AROMATIC-CATIONIC PEPTIDES AND USES OF SAME 2012-12-05 2014-10-02
US2016264623 TETRAPEPTIDE COMPOUND AND METHOD FOR PRODUCING SAME 2014-10-23 2016-09-15
US2017081363 PHARMACEUTICALLY RELEVANT AROMATIC-CATIONIC PEPTIDES 2014-12-23
US2016340389 PHARMACEUTICALLY RELEVANT AROMATIC-CATIONIC PEPTIDES 2014-12-23
US2017129920 Process for Preparing D-Arginyl-2, 6-Dimethyl-L-Tyrosyl-L-Lysyl-L-Phenylalaninamide 2015-06-24

REFERENCES

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2: Szeto HH, Birk AV. Serendipity and the discovery of novel compounds that restore mitochondrial plasticity. Clin Pharmacol Ther. 2014 Dec;96(6):672-83. doi: 10.1038/clpt.2014.174. Epub 2014 Sep 4. Review. PubMed PMID: 25188726; PubMed Central PMCID: PMC4267688.

3: Dai W, Shi J, Gupta RC, Sabbah HN, Hale SL, Kloner RA. Bendavia, a mitochondria-targeting peptide, improves postinfarction cardiac function, prevents adverse left ventricular remodeling, and restores mitochondria-related gene expression in rats. J Cardiovasc Pharmacol. 2014 Dec;64(6):543-53. PubMed PMID: 25165999.

4: Eirin A, Ebrahimi B, Zhang X, Zhu XY, Woollard JR, He Q, Textor SC, Lerman A, Lerman LO. Mitochondrial protection restores renal function in swine atherosclerotic renovascular disease. Cardiovasc Res. 2014 Sep 1;103(4):461-72. doi: 10.1093/cvr/cvu157. Epub 2014 Jun 19. PubMed PMID: 24947415; PubMed Central PMCID: PMC4155472.

5: Liu S, Soong Y, Seshan SV, Szeto HH. Novel cardiolipin therapeutic protects endothelial mitochondria during renal ischemia and mitigates microvascular rarefaction, inflammation, and fibrosis. Am J Physiol Renal Physiol. 2014 May 1;306(9):F970-80. doi: 10.1152/ajprenal.00697.2013. Epub 2014 Feb 19. PubMed PMID: 24553434.

6: Brown DA, Hale SL, Baines CP, del Rio CL, Hamlin RL, Yueyama Y, Kijtawornrat A, Yeh ST, Frasier CR, Stewart LM, Moukdar F, Shaikh SR, Fisher-Wellman KH, Neufer PD, Kloner RA. Reduction of early reperfusion injury with the mitochondria-targeting peptide bendavia. J Cardiovasc Pharmacol Ther. 2014 Jan;19(1):121-32. doi: 10.1177/1074248413508003. Epub 2013 Nov 28. PubMed PMID: 24288396; PubMed Central PMCID: PMC4103197.

7: Birk AV, Chao WM, Bracken C, Warren JD, Szeto HH. Targeting mitochondrial cardiolipin and the cytochrome c/cardiolipin complex to promote electron transport and optimize mitochondrial ATP synthesis. Br J Pharmacol. 2014 Apr;171(8):2017-28. doi: 10.1111/bph.12468. PubMed PMID: 24134698; PubMed Central PMCID: PMC3976619.

8: Szeto HH. First-in-class cardiolipin-protective compound as a therapeutic agent to restore mitochondrial bioenergetics. Br J Pharmacol. 2014 Apr;171(8):2029-50. doi: 10.1111/bph.12461. Review. PubMed PMID: 24117165; PubMed Central PMCID: PMC3976620.

9: Zhao WY, Han S, Zhang L, Zhu YH, Wang LM, Zeng L. Mitochondria-targeted antioxidant peptide SS31 prevents hypoxia/reoxygenation-induced apoptosis by down-regulating p66Shc in renal tubular epithelial cells. Cell Physiol Biochem. 2013;32(3):591-600. doi: 10.1159/000354463. Epub 2013 Sep 6. PubMed PMID: 24021885.

10: Dai DF, Hsieh EJ, Chen T, Menendez LG, Basisty NB, Tsai L, Beyer RP, Crispin DA, Shulman NJ, Szeto HH, Tian R, MacCoss MJ, Rabinovitch PS. Global proteomics and pathway analysis of pressure-overload-induced heart failure and its attenuation by mitochondrial-targeted peptides. Circ Heart Fail. 2013 Sep 1;6(5):1067-76. doi: 10.1161/CIRCHEARTFAILURE.113.000406. Epub 2013 Aug 9. PubMed PMID: 23935006; PubMed Central PMCID: PMC3856238.

/////////////////////Elamipretide,  SS-31,  Bendavia, PEPTIDE

CC1=CC(=CC(=C1CC(C(=O)NC(CCCCN)C(=O)NC(CC2=CC=CC=C2)C(=O)N)NC(=O)C(CCCN=C(N)N)N)C)O

RAPASTINEL, рапастинел , راباستينيل , 雷帕替奈


File:Rapastinel.svg

Rapastinel.pngImage result for RAPASTINEL

ChemSpider 2D Image | Rapastinel | C18H31N5O6

RAPASTINEL

  • Molecular Formula C18H31N5O6
  • Average mass 413.469 Da

L-threonyl-L-prolyl-L-prolyl-L-threoninamide

(2S)-1-[(2S)-1-[(2S,3R)-2-amino-3-hydroxybutanoyl]pyrrolidine-2-carbonyl]-N-[(2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl]pyrrolidine-2-carboxamide

117928-94-6 [RN]
L-Threoninamide, L-threonyl-L-prolyl-L-prolyl-
рапастинел [Russian]
راباستينيل [Arabic]
雷帕替奈 [Chinese]
(S)-N-((2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl)-1-((S)-1-((2S,3R)-2-amino-3-hydroxybutanoyl)pyrrolidine-2-carbonyl)pyrrolidine-2-carboxamide

UNII-6A1X56B95E; 117928-94-6; 6A1X56B95E

(S)-N-((2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl)-1-((S)-1-((2S,3R)-2-amino-3-hydroxybutanoyl)pyrrolidine-2-carbonyl)pyrrolidine-2-carboxamide
[117928-94-6]
GLYX-13 trifluoroacetate
GLYX-13;GLYX13;GLYX 13;Thr-Pro-Pro-Thr-NH2
L-Threonyl-L-prolyl-L-prolyl-L-threoninamide trifluoroacetate
MFCD20527320
Thr-Pro-Pro-Thr-NH2 trifluoroacetate
TPPT-amide trifluoroacetate
UNII:6A1X56B95E

BV-102; GLYX13, GLYX-13, in phase 3 clinical trials

Treatment of major depressive disorder – Phase 3 Allergan

Fast Track designation
Originator 
Northwestern University

  • Developer Allergan; Naurex
  • Class Amides; Antidepressants; Neuropsychotherapeutics; Oligopeptides; Small molecules
  • Mechanism of Action NR2B N-Methyl-D-Aspartate receptor agonists

Highest Development Phases

  • Phase III Major depressive disorder
  • Discontinued Bipolar depression; Neuropathic pain

Most Recent Events

  • 01 Jan 2017 Allergan initiates enrolment in a phase III trial for Major depressive disorder (Adjunctive treatment) in USA (IV, Injection) (NCT03002077)
  • 21 Dec 2016 Allergan plans a phase III trial for Major depressive disorder (Adjunctive treatment) in USA (IV, Injection) (NCT03002077)
  • 01 Nov 2016 Phase-III clinical trials in Major depressive disorder (Adjunctive treatment, Prevention of relapse) in USA (IV) (NCT02951988)Image result for RAPASTINELImage result for RAPASTINEL

It is disclosed that GLYX-13 (Rapastinel) acts as NMDA receptor partial agonist, useful for treating neurodegenerative disorders such as stroke-related brain cell death, convulsive disorders, and learning and memory. See WO2015065891 , claiming peptidyl compound. Naurex , a subsidiary of Allergan is developing rapastinel (GLYX-13) (in phase3 clinical trials), a rapid-acting monoclonal antibody-derived tetrapeptide and NMDA receptor glycine site functional partial agonist as well as an amidated form of NT-13, for treating depression.

Rapastinel (INN) (former developmental code names GLYX-13BV-102) is a novel antidepressant that is under development by Allergan (previously Naurex) as an adjunctive therapy for the treatment of treatment-resistant major depressive disorder.[1][2] It is a centrally activeintravenously administered (non-orally activeamidated tetrapeptide (Thr-Pro-Pro-Thr-NH2) that acts as a selective, weak partial agonist (mixed antagonist/agonist) of an allosteric site of the glycine site of the NMDA receptor complex (Emax ≈ 25%).[1][2]The drug is a rapid-acting and long-lasting antidepressant as well as robust cognitive enhancer by virtue of its ability to both inhibit and enhance NMDA receptor-mediated signal transduction.[1][2]

On March 3, 2014, the U.S. FDA granted Fast Track designation to the development of rapastinel as an adjunctive therapy in treatment-resistant major depressive disorder.[3] As of 2015, the drug had completed phase II clinical development for this indication.[4] On January 29, 2016, Allergan (who acquired Naurex in July 2015) announced that rapastinel had received Breakthrough Therapydesignation from the U.S. FDA for adjunctive treatment of major depressive disorder.

Rapastinel belongs to a group of compounds, referred to as glyxins (hence the original developmental code name of rapastinel, GLYX-13),[5] that were derived via structural modification of B6B21, a monoclonal antibody that similarly binds to and modulates the NMDA receptor.[2][6][7] The glyxins were invented by Joseph Moskal, the co-founder of Naurex.[5] Glyxins and B6B21 do not bind to the glycine site of the NMDA receptor but rather to a different regulatory site on the NMDA receptor complex that serves to allosterically modulate the glycine site.[8] As such, rapastinel is technically an allosteric modulator of the glycine site of the NMDA receptor, and hence is more accurately described as a functional glycine site weak partial agonist.[8]

In addition to its antidepressant effects, rapastinel has been shown to enhance memory and learning in both young adult and learning-impaired, aging rat models.[9] It has been shown to increase Schaffer collateralCA1 long-term potentiation in vitro. In concert with a learning task, rapastinel has also been shown to elevate gene expression of hippocampal NR1, a subunit of the NMDA receptor, in three-month-old rats.[10] Neuroprotective effects have also been demonstrated in Mongolian Gerbils by delaying the death of CA1, CA3, and dentate gyrus pyramidal neurons under glucose and oxygen-deprived conditions.[11] Additionally, rapastinel has demonstrated antinociceptive activity, which is of particular interest, as both competitive and noncompetitive NMDA receptor antagonists are ataxic at analgesic doses, while rapastinel and other glycine subunit ligands are able to elicit analgesia at non-ataxic doses.[12]

Apimostinel (NRX-1074), an analogue of rapastinel with the same mechanism of action but dramatically improved potency, is being developed by the same company as a follow-on compound to rapastinel.

CN 104109189,

PAPER

Tetrahedron Letters (2017), 58(16), 1568-1571

http://www.sciencedirect.com/science/article/pii/S0040403917303015

Novel silaproline (Sip)-incorporated close structural mimics of potent antidepressant peptide drug rapastinel (GLYX-13)

Highlights

Structural mimics of rapastinel comprising silaproline is reported.

Sip introduction is expected to improve its pharmacokinetic profiles.

Standard peptide coupling strategy in the solution-phase is utilized for synthesis.

Abstract

Rapastinel (GLYX-13) is a C-amidated tetrapeptide drug under clinical development for adjunctive treatment of major depressive disorder (MDD). Rapastinel features two consecutive proline residues centered at the peptide sequence (Thr-Pro-Pro-Thr-NH2), which are detrimental to its biological activity. In this communication, we report the synthesis of very close structural analogues of rapastinel comprising silaproline (Sip) as proline surrogate. By virtue of its enhanced lipophilicity and metabolic stability, Sip introduction in the native rapastinel sequence is expected to improve its pharmacokinetic profiles.

Graphical abstract

This paper reports the synthesis of silaproline (Sip)-incorporated close structural mimics of potent antidepressant peptide drug rapastinel (GLYX-13).

Unlabelled figure

PATENT

CN 104109189

Depression is the most common neuropsychiatric diseases, seriously affecting people’s health. In China With accelerated pace of life, increasing the incidence of depression was significantly higher social pressure.

[0003] Drug therapy is the primary means of treatment of depression. The main treatment drugs, including tricyclic antidepressants such as imipramine, amitriptyline and the like; selective serotonin reuptake inhibitors such as fluoxetine, sertraline and the like; serotonin / norepinephrine dual uptake inhibitors such as venlafaxine, duloxetine. However, commonly used drugs slow onset, usually takes several weeks to months, and there is not efficient and toxicity obvious shortcomings.

[0004] GLYX-13 is a new antidepressant, Phase II clinical study is currently underway. It does this by regulating the brain NMDA (N_ methyl -D- aspartate) receptors play a role, and none of them have serious side effects such as ketamine and R-rated, such as hallucinations and schizophrenia and so on.GLYX-13 can play a strong, fast and sustained antidepressant effects, the onset time of less than 24 hours, and the sustainable average of 7 days. As a peptide drug, GLYX-13 was well tolerated and safe to use.

[0005] GLYX-13 is a tetrapeptide having the sequence structure Thr-Pro-Pro-Thr, which is a free N-terminal amino group, C terminal amide structure. GLYX-13 synthesis methods include traditional methods of two solid-phase peptide synthesis and liquid phase peptide synthesis, because of its short sequence, the amount of solid phase synthesis of amino acids, high cost, and difficult to achieve a lot of preparation. A small amount of liquid phase amino acids, high yield can be prepared in large quantities.

The present invention can be further described by the following examples.

Preparation of r-NH2; [0013] Example 1 Four peptide H-Thr-Pr〇-P; r〇-Th

[0014] 1.1 threonine carboxyl amidation (H-Thr-NH2)

[0015] 500ml three flask was added Boc-Thr (tBu) -0H20g (0.073mol), anhydrous tetrahydrofuran (THF) 150ml, stirring to dissolve the solid. Ice-salt bath cooled to -10 ° C~_15 ° C, was added N- methylmorpholine 8ml, then l〇ml isobutyl chloroformate, keeping the temperature not higher than -10 ° C, after the addition was complete retention low temperature reaction 10min, then adding ammonia 20ml, ice bath reaction 30min, then at room temperature the reaction 8h. The reaction was stopped, water 300ml, 200ml ethyl acetate was added to extract the precipitate, washed with water 3 times.Dried over anhydrous sodium sulfate 6h. Filtered, and then the solvent was distilled off under reduced pressure to give a white solid 16. 6g, 83% yield.

[0016] The above product was dissolved in 50ml of trifluoroacetic acid or 2N hydrochloric acid / ethyl acetate solution was reacted at room temperature lh, the solvent was distilled off to give a white solid, i.e. amidated carboxyl threonine trifluoroacetic acid / hydrochloric acid salt H- Thr-NH 2. HC1.

[0017] 1.2 Pro – Preparation of threonine dipeptide fragment H-Pr〇-Thr-NH2 of

[0018] 500ml flask was added Boc-Pr〇 three-0H20g (0. 093mol), in anhydrous tetrahydrofuran (TH F) 200ml, stirring to dissolve solids, cooled to ice-salt bath -l〇 ° C~-15 ° C, added N- methylmorpholine 11ml, then dropwise isobutyl 13ml, keeping the temperature not higher than -10 ° C, keep it cool after the addition was complete the reaction 10min. H-Thr-NH2. HC114. 5g dissolved in 50ml of tetrahydrofuran, was added N- methyl morpholine 11ml. The above solution was added to the reaction mixture, the low temperature reaction 30min, then at room temperature the reaction 8h. The reaction was stopped, water 300ml, 200ml ethyl acetate was added to extract the precipitate, washed with water 3 times. Dried over anhydrous sodium sulfate 6h. Filtered and then evaporated under reduced pressure to give a white solid 25.7g, 82% yield.

[0019] The above product was dissolved in 100ml of 2N trifluoroacetic acid or hydrochloric acid / ethyl acetate solution was reacted at room temperature lh, the solvent was distilled off to give a white solid, i.e., proline – threonine dipeptide hydrochloride salt of H-Pr〇 -Thr-NH 2. HC1.

[0020] The above product was dissolved in 100ml of pure water, sodium carbonate solution was added to adjust the PH value, the precipitated white solid was filtered and dried in vacuo to give the desired product proline – threonine dipeptide fragment H-Pr square-Thr- NH223g.

Protected threonine [0021] 1.3 – Preparation of dipeptide fragment Boc-Thr (tBu) -Pr〇-0H of

[0022] Boc-Thr (tBu) -0H20g (0 · 073mol) was dissolved in dry tetrahydrofuran (THF) 150ml, stirring to dissolve the solid.Ice-salt bath cooled to -10 G~-15 ° C, was added N- methylmorpholine 8ml, then dropwise isobutyl 10ml, maintained at a temperature no higher than -10 ° C, kept cold reaction After dropping 10min. Proline methyl ester hydrochloride

PAPER

Journal of Medicinal Chemistry (1989), 32(10), 2407-11.

Threonylprolylprolylthreoninamide (HRP-7). The synthesis of HRP-7 was begun with 3 g of p-methylbenzhydrylamine-resin containing 1.41 mmol of attachment sites. The protected tetrapeptidyl-resin (1.63 g) was subjected to HF cleavage. Radioactivity was found in the 1% acetic acid extract (77%) and in the 5% extract (24%). These solutions were combined and lyophilized. Crude peptide (309 mg, 97%) was gel filtered on Sephadex G-15 (1.1 X 100 cm). Peptide eluting between 34 and 46 mL was pooled and lyophilized to yield 294 mg (95%, overall yield 92%) of homogeneous HRP-7.

PATENT

WO 2010033757

PATENT

WO 2017136348

Process for synthesizing dipyrrolidine peptide compounds (eg GLYX-13) is claimed.

An N-methyl-D-aspartate (NMDA) receptor is a postsynaptic, ionotropic receptor that is responsive to, inter alia, the excitatory amino acids glutamate and glycine and the synthetic compound NMDA. The NMDA receptor (NMDAR) appears to controls the flow of both divalent and monovalent ions into the postsynaptic neural cell through a receptor associated channel and has drawn particular interest since it appears to be involved in a broad spectrum of CNS disorders. The NMDAR has been implicated, for example, in neurodegenerative disorders including stroke-related brain cell death, convulsive disorders, and learning and memory.

NMDAR also plays a central role in modulating normal synaptic transmission, synaptic plasticity, and excitotoxicity in the central nervous system. The NMDAR is further involved in Long-Term Potentiation (LTP), which is the persistent strengthening of neuronal connections that underlie learning and memory The NMDAR has been associated with other disorders ranging from hypoglycemia and cardiac arrest to epilepsy. In addition, there are preliminary reports indicating involvement of NMDA receptors in the chronic neurodegeneration of Huntington’s, Parkinson’s, and Alzheimer’s diseases. Activation of the NMDA receptor has been shown to be responsible for post-stroke convulsions, and, in certain models of epilepsy, activation of the NMDA receptor has been shown to be necessary for the generation of seizures. In addition, certain properties of NMDA receptors suggest that they may be involved in the information-processing in the brain that underlies consciousness itself. Further, NMDA receptors have also been implicated in certain types of spatial learning.

[0003] In view of the association of NMDAR with various disorders and diseases, NMDA-modulating small molecule agonist and antagonist compounds have been developed for therapeutic use. NMDA receptor compounds may exert dual (agonist/antagonist) effect on the NMDA receptor through the allosteric sites. These compounds are typically termed “partial agonists”. In the presence of the principal site ligand, a partial agonist will displace some of the ligand and thus decrease Ca flow through the receptor. In the absence of the principal site ligand or in the presence of a lowered level of the principal site ligand, the partial agonist acts to increase Ca++ flow through the receptor channel.

Example 2: Synthesis of GLYX-13

[00119] GLYX-13 was prepared as follows, using intermediates KSM-1 and KSM-2 produced in Example 1. The synthetic route for the same is provided in Figure 2.

Stage A – Preparation of (S)-N-((2S, 3R)-l-amino-3-hydroxy-l-oxobutan-2-yl)-l-((S)-pyrrolidine-2-carbonyl) pyrrolidine-2-carboxamide (Compound XI)

[00120] In this stage, KSM -1 was reacted with 10%Pd/C in presence of methanol to produce a compound represented by Formula XI. The reaction was optimized and performed up to 4.0 kg scale in the production plant and observed consistent quality (>80% by HPLC%PA) and yields (80% to 85%).

[00121] The reaction scheme involved in this method is as follows:

[00122] Raw materials used for this method are illustrated in Table 7 as follows:

Table 7.

[00123] In stage A, 10% Palladium on Carbon (w/w, 50% wet) was charged into the pressure reactor at ambient temperature under nitrogen atmosphere. KSM-1 was dissolved in methanol in another container and sucked into above reactor under vacuum. Hydrogen pressure was maintained at 45-60 psi at ambient temperature for over a period of 5-6 hrs. Progress of the reaction mixture was monitored by HPLC for KSM-1 content; limit is not more than 5%.

Hyflow bed was prepared with methanol (Lot-II). The reaction mass was filtered through nutsche filter under nitrogen atmosphere and bed was washed with Methanol Lot-Ill. Filtrate was transferred into the reactor and distilled completely under reduced pressure at below 50 °C (Bath temperature) to get the syrup and syrup material was unloaded into clean and dry container and samples were sent to QC for analysis.

[00124] From the above reaction(s), 1.31 kg of compound represented by Formula XI was obtained with a yield of 89.31% and with a purity of 93.63%).

Stage B – Preparation of Benzyl (2S, 3R)-l-((S)-2-((S)-2-((2S, 3R)-I-amino-3-hydroxy-I- oxobutan-2-ylcarbamoyl) pyrrolidine-! -carbonyl) pyrrolidin-1 -yl)-3-hydroxy-l -oxobutan-2- ylcarbamate (Compound XII)

[00125] In this stage the compound represented by Formula XI obtained above was reacted with KSM-2 to produce a compound represented by Formula XII. This reaction was optimized and scaled up to 3.0 kg scale in the production plant and obtained 25% to 28% yields with UPLC purity (>95%).

[00126] The reaction scheme is as follows:

[00127] Raw materials used for this method are illustrated in Table 8 as follows:

Table 8.

[00128] Stage B: ethanol was charged into the reactor at 20 to 35 °C. Compound represented by Formula XI was charged into the reactor under stirring at 20 to 35 °C and reaction mass was cooled to -5 to 0°C. EDC.HC1 was charged into the reaction mass at -5 to 0 °C and reaction mass, was maintained at -5 to 0 °C for 10-15 minutes. N-Methyl morpholine was added drop wise to the above reaction mass at -5 to 0 °C and reaction mass was maintained at -5 to 0 °C for 10-15 minutes.

[00129] KSM-2 was charged into the reactor under stirring at -5 to 0 °C and reaction mass was maintained at -5 to 0 °C for 3.00 to 4.00 hours. The temperature of the reaction mass was raised to 20 to 35 °C and was maintained at 20 to 35 °C for 12 – 15 hours under stirring. (Note:

Monitor the reaction mass by HPLC for Stage A content after 12.0 hours and thereafter every 2.0 hours. The content of stage A should not be more than 2.0%). Ethanol was distilled out completely under vacuum at below 50 °C (Hot water temperature) and reaction mass was cooled to 20 to 35 °C. Water Lot-1 was charged into the residue obtained followed by 10% DCM-Isopropyl alcohol (Mixture of Dichloromethane Lot-1 & Isopropyl alcohol Lot-1 prepared in a cleaned HDPE container) into the reaction mass at 20 – 35 °C.

[00130] Both the layers were separated and the aqueous layer was charged into the reactor. 10%) DCM-Isopropyl alcohol (Mixture of Dichloromethane Lot-2 & Isopropyl alcohol Lot-2 prepared in a cleaned HDPE container) was charged into the reaction mass at 20 to 35 °C. Both the layers were separated and the aqueous layer was charged back into the reactor. 10%> IDCM-isopropyl alcohol (Mixture of Dichloromethane Lot-3 & Isopropyl alcohol Lot-3 prepared in a cleaned HDPE container) was charged into the reaction mass at 20 to 35 °C. Both the layers were separated and the aqueous layer was charged back into the reactor. 10%> DCM-Isopropyl alcohol (Mixture of Dichloromethane Lot-4 & Isopropyl alcohol Lot-4 prepared in a cleaned HDPE container) was charged into the reaction mass at 20 to 35 °C and separated both the layers. The above organic layers were combined and potassium hydrogen sulfate solution (Prepare a solution in a HDPE container by dissolving Potassium hydrogen sulfate Lot-1 in water Lot-2) was charged into the reaction mass at 20 to 35 °C. Separated both the layers and charged back organic layer into the reactor. Potassium hydrogen sulfate solution (Prepared a solution in a HDPE container by dissolving Potassium hydrogen sulfate Lot-2 in water Lot-3) was charged into the reaction mass at 20 to 35 °C. Separated both the layers and the organic layer was dried over Sodium sulfate and distilled out the solvent completely under vacuum at below 45 °C (Hot water temperature).

[00131] The above crude was absorbed with silica gel (100-200mesh) Lot-1 in

dichloromethane. Prepared the column with silica gel (100-200 mesh) Lot-2, and washed the silica gel bed with from Dichloromethane Lot-5 and charged the adsorbed compound into the column. Eluted the column with 0-10% Methanol Lot-1 in Dichloromethane Lot-5 and analyzed fractions by HPLC. Solvent was distilled out completely under vacuum at below 45 °C (Hot water temperature). Methyl tert-butyl ether Lot-1 was charged and stirred for 30 min. The solid was filtered through the Nutsche filter and washed with Methyl tert-butyl ether Lot-2 and

samples were sent to QC for complete analysis. (Note: If product quality was found to be less than 95%, column purification should be repeated).

[00132] From the above reaction(s), 0.575 kg of compound represented by Formula XII was obtained with a yield of 17% and with a purity of 96.28%).

Stage C – Preparation of Benzyl (S)-N-((2S, 3R)-l-amino-3-hydroxy-l-oxobutan-2-yl)-l-((S)-l- ((2R, 3R)-2-amino-3-hydroxybutanoyl) pyrrolidine-2 carbonyl) pyrrolidine-2-carboxamide (GLYX-13)

[00133] In this reaction step the compound of Formula XII obtained above was reacted with 10%oPd in presence of methanol to produce GLYX-13. This reaction was optimized and performed up to 2.8 kg scale in the production plant and got 40% to 45% of yields with UPLC purity >98%.

[00134] The reaction scheme involved in this method is as follows:

i

[00135] Raw materials used for this method are illustrated in Table 9 as follows:

Table 9.

30 Nitrogen cylinder – – – – – 31 Hydrogen cylinder – – – – –

[00136] In an exemplary embodiment of stage C, 10% Palladium Carbon (50% wet) was charged into the pressure reactor at ambient temperature under nitrogen atmosphere. Compound of Formula XII was dissolved in methanol in a separate container and sucked into the reactor under vacuum. Hydrogen pressure was maintained 45-60 psi at ambient temperature over a period of 6-8 hrs. Progress of the reaction was monitored by HPLC for stage-B (compound represented by Formula XII) content (limit is not more than 2%). If HPLC does not comply continue the stirring until it complies. Prepared the hyflow bed with methanol (Lot-II) and the reaction mass was filtered through hyflow bed under nitrogen atmosphere, and the filtrate was collected into a clean HDPE container. The bed was washed with Methanol Lot-Ill and the filtrate was transferred into the Rota Flask and distilled out the solvent completely under reduced pressure at below 50°C (Bath temperature) to get the crude product. The material was unloaded into clean HDPE container under Nitrogen atmosphere.

[00137] Neutral Alumina Lot-1 was charged into the above HDPE container till uniform mixture was formed. The neutral Alumina bed was prepared with neutral alumina Lot-2 and dichloromethane Lot-1 in a glass column. The neutral Alumina Lot-3 was charged and

Dichloromethane Lot-2 into the above prepared neutral Alumina bed. The adsorbed compound was charged into the column from op.no.11. The column was eluted with Dichloromethane Lot-2 and collect 10 L fractions. The column was eluted with Dichloromethane Lot-3 and collected 10 L fractions. The column was eluted with Dichloromethane Lot-4 and Methanol Lot-4 (1%) and collected 10 L fractions. The column was eluted with Dichloromethane Lot-5 and Methanol Lot-5 (2%) and collected 10 L fractions. The column was eluted with Dichloromethane Lot-6 and Methanol Lot-6 (3%) and collected 10 L fractions. The column was eluted with

Dichloromethane Lot-7 and Methanol Lot-7 (5%). and collected 10 L fractions. The column was eluted with Dichloromethane Lot-8 and Methanol Lot-8 (8%). and collected 10 L fractions. The column was eluted with Dichloromethane Lot-9 and Methanol Lot-9 (10%) and collected 10 L fractions. Fractions were analyzed by HPLC (above 97% purity and single max impurity >0.5% fractions are pooled together)

[00138] Ensured the reactor is clean and dry. The pure fractions were transferred into the reactor.

[00139] The solvent was distilled off completely under vacuum at below 45 °C (Hot water temperature). The material was cooled to 20 to 35°C. Charged Dichloromethane Lot- 10 and Methanol Lot- 10 into the material and stirred till dissolution. Activated carbon was charged into the above mixture at 20 to 35°C and temperature was raised to 45 to 50 °C.

[00140] Prepared the Hyflow bed with Hyflow Lot-2 and Methanol Lot-11 Filtered the reaction mass through the Hy-flow bed under nitrogen atmosphere and collect the filtrate into a clean FIDPE container. Prepared solvent mixture with Dichloromethane Lot-11 and Methanol Lot- 12 in a clean FIDPE container and washed Nutsche filter with same solvent. Charged filtrate in to Rota evaporator and distilled out solvent under vacuum at below 50°C. Dry the compound in Rota evaporator for 5 to 6 hours at 50°C, send sample to QC for Methanol content (residual solvent) which should not be more than 3000 ppm. The material was cooled to 20 to 35 °C and the solid material was unloaded into clean and dry glass bottle. Samples were sent to QC for complete analysis.

[00141] From the above reaction(s), 0.92 kg of Glyx-13 was obtained with a yield of 43.5% and with a purity of 99.73%.

Patent ID

Patent Title

Submitted Date

Granted Date

US9593145 SECONDARY STRUCTURE STABILIZED NMDA RECEPTOR MODULATORS AND USES THEREOF 2015-05-14 2016-04-28
US2017049844 STABLE COMPOSITIONS OF NEUROACTIVE PEPTIDES 2015-04-27
US2017049845 METHODS OF TREATING ALZHEIMER’S DISEASE, HUNTINGTON’S DISEASE, AUTISM, OR OTHER DISORDERS 2016-04-14
US2017072005 COMBINATIONS OF NMDAR MODULATING COMPOUNDS 2015-05-06
US2016345855 METHODS OF TREATING BRAIN DISORDERS OR IDENTIFYING BIOMARKERS RELATED THERETO 2014-12-15
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US2015182582 Methods of Treating Depression and Other Related Diseases 2014-08-05 2015-07-02
US2015253305 METHODS OF IDENTIFYING COMPOUNDS FOR TREATING DEPRESSION AND OTHER RELATED DISEASES 2013-10-11 2015-09-10
US2015343013 METHODS OF TREATING NEUROPATHIC PAIN 2014-12-16 2015-12-03
US2016002292 METHODS OF TREATING DEPRESSION AND OTHER RELATED DISEASES 2015-02-06 2016-01-07
US2016244485 NMDA RECEPTOR MODULATORS AND PRODRUGS, SALTS, AND USES THEREOF 2014-10-27 2016-08-25
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US2013296248 Methods of Treating Depression and Other Related Diseases 2013-07-09 2013-11-07
US9101612 Secondary Structure Stabilized NMDA Receptor Modulators and Uses Thereof 2011-02-11 2013-02-28
US2012178695 METHODS OF TREATING NEUROPATHIC PAIN 2010-07-02 2012-07-12
US8951968 Methods of treating depression and other related diseases 2012-04-05 2015-02-10
US8492340 Methods of treating depression and other related diseases 2012-09-10 2013-07-23
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US8673843 NMDA receptors modulators and uses thereof 2012-06-18 2014-03-18
US2014249088 METHODS OF TREATING NEUROPATHIC PAIN 2013-09-27 2014-09-04
US9198948 Methods of Treating Depression and Other Related Diseases 2013-07-09 2013-11-21
US9149501 Methods of Treating Depression and Other Related Diseases 2013-07-09 2013-11-28
US9340576 Methods of Treating Depression and Other Related Diseases 2013-06-04 2013-10-31

See also

References

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  2. Jump up to:a b c d Moskal JR, Burgdorf JS, Stanton PK, Kroes RA, Disterhoft JF, Burch RM, Amin Khan M (2016). “The Development of Rapastinel (Formerly GLYX-13); a rapid acting and long lasting antidepressant”. Curr NeuropharmacolPMID 26997507.
  3. Jump up^ FDA Grants Fast Track Designation to Naurex’s Rapid-Acting Novel Antidepressant GLYX-13 http://www.prnewswire.com/news-releases/fda-grants-fast-track-designation-to-naurexs-rapid-acting-novel-antidepressant-glyx-13-248174561.html
  4. Jump up^ http://naurex.com/wp-content/uploads/2014/12/Naurex_P2b_Data_Press_Release_FINAL_Approved.pdf
  5. Jump up to:a b Burgdorf, Jeffrey; Zhang, Xiao-lei; Weiss, Craig; Matthews, Elizabeth; Disterhoft, John F.; Stanton, Patric K.; Moskal, Joseph R. (2011). “The N-methyl-d-aspartate receptor modulator GLYX-13 enhances learning and memory, in young adult and learning impaired aging rats”Neurobiology of Aging32 (4): 698–706. ISSN 0197-4580PMC 3035742Freely accessiblePMID 19446371doi:10.1016/j.neurobiolaging.2009.04.012.
  6. Jump up^ Haring R, Stanton PK, Scheideler MA, Moskal JR (1991). “Glycine-like modulation of N-methyl-D-aspartate receptors by a monoclonal antibody that enhances long-term potentiation”. J. Neurochem57 (1): 323–32. PMID 1828831doi:10.1111/j.1471-4159.1991.tb02131.x.
  7. Jump up^ Moskal JR, Kuo AG, Weiss C, Wood PL, O’Connor Hanson A, Kelso S, Harris RB, Disterhoft JF (2005). “GLYX-13: a monoclonal antibody-derived peptide that acts as an N-methyl-D-aspartate receptor modulator”. Neuropharmacology49 (7): 1077–87. PMID 16051282doi:10.1016/j.neuropharm.2005.06.006.
  8. Jump up to:a b Burch RM, Amin Khan M, Houck D, Yu W, Burgdorf J, Moskal JR (2016). “NMDA Receptor Glycine Site Modulators as Therapeutics for Depression: Rapastinel has Antidepressant Activity without Causing Psychotomimetic Side Effects”. Curr NeuropharmacolPMID 26830963.
  9. Jump up^ Burgdorf, Jeffrey; Zhang, Xiao-lei; Weiss, Craig; Matthews, Elizabeth; Disterhoft, John F.; Stanton, Patric K.; Moskal, Joseph R. (2011). “The N-methyl-d-aspartate receptor modulator GLYX-13 enhances learning and memory, in young adult and learning impaired aging rats”Neurobiology of Aging32 (4): 698–706. PMC 3035742Freely accessiblePMID 19446371doi:10.1016/j.neurobiolaging.2009.04.012.
  10. Jump up^ Moskal, Joseph R.; Kuo, Amy G.; Weiss, Craig; Wood, Paul L.; O’Connor Hanson, Amy; Kelso, Stephen; Harris, Robert B.; Disterhoft, John F. (2005). “GLYX-13: A monoclonal antibody-derived peptide that acts as an N-methyl-d-aspartate receptor modulator”. Neuropharmacology49 (7): 1077–87. PMID 16051282doi:10.1016/j.neuropharm.2005.06.006.
  11. Jump up^ Stanton, Patric K.; Potter, Pamela E.; Aguilar, Jennifer; Decandia, Maria; Moskal, Joseph R. (2009). “Neuroprotection by a novel NMDAR functional glycine site partial agonist, GLYX-13”. NeuroReport20 (13): 1193–7. PMID 19623090doi:10.1097/WNR.0b013e32832f5130.
  12. Jump up^ Wood, Paul L.; Mahmood, Siddique A.; Moskal, Joseph R. (2008). “Antinociceptive action of GLYX-13: An N-methyl-D-aspartate receptor glycine site partial agonist”. NeuroReport19(10): 1059–61. PMID 18580579doi:10.1097/WNR.0b013e32830435c9.

External links

rapastinel
Rapastinel.svg
GLYX-133DanFrame1.svg
Clinical data
Pregnancy
category
  • US: N (Not classified yet)
ATC code
  • none
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
ChemSpider
Chemical and physical data
Formula C18H31N5O6
Molar mass 413.47 g/mol
3D model (JSmol)
Patent ID

Patent Title

Submitted Date

Granted Date

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2015-02-06
2016-01-07
Patent ID

Patent Title

Submitted Date

Granted Date

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2013-07-09
2013-11-21
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2014-12-15
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2013-07-09
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2013-07-09
2013-11-28
Patent ID

Patent Title

Submitted Date

Granted Date

US2017072005 COMBINATIONS OF NMDAR MODULATING COMPOUNDS
2015-05-06
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2015-04-27
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2012-06-18
2014-03-18
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2013-09-27
2014-09-04
Patent ID

Patent Title

Submitted Date

Granted Date

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2015-07-24
US8492340 Methods of treating depression and other related diseases
2012-09-10
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/////////////RAPASTINEL, BV-102, GLYX-13, PEPTIDE, phase 3, рапастинел , راباستينيل , 雷帕替奈 , Fast Track designation , allergan, Peptide Drugs, 

CC(C(C(=O)N1CCCC1C(=O)N2CCCC2C(=O)NC(C(C)O)C(=O)N)N)O

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