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ORGANIC SPECTROSCOPY

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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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EpiVacCorona


Russia approves 2nd coronavirus vaccine "EpiVacCorona"

Origin of EpiVacCorona antigenes

  1. MKIEEGKLVIWINGDKGYNGLAEVGKKFEKDTGIKVTVEHPDKLEEKFPQVAATGDGPDIIFWAHDRFGGYAQSGLLAEITPDKAFQDKLYPFTWDAVRYNGKLIAYPIAVEALSLIYNKDLLPNPPKTWEEIPALDKELKAKGKSALMFNLQEPYFTWPLIAADGGYAFKYENGKYDIKDVGVDNAGAKAGLTFLVDLIKNKHMNADTDYSIAEAAFNKGETAMTINGPWAWSNIDTSKVNYGVTVLPTFKGQPSKPFVGVLSAGINAASPNKELAKEFLENYLLTDEGLEAVNKDKPLGAVALKSYEEELAKDPRIAATMENAQKGEIMPNIPQMSAFWYAVRTAVINAASGRQTVDEALKDAQTNSSSNNNNNNNNNNLGDNGPQNQRNAPRITFGGPSDSTGSNQNGERSGARSKQRRPQGLPNNTASWFTALTQHGKEDLKFPRGQGVPINTNSSPDDQIGYYRRATRRIRGGDGKMKDLSPRWYFYYLGTGPEAGLPYGANKDGIIWVATEGALNTPKDHIGTRNPANNAAIVLQLPQGTTLPKGFYAEGSRGGSQASSRSSSRSRNSSRNSTPGSSRGTSPARMAGNGGDAALALLLLDRLNQLESKMSGKGQQQQGQTVTKKSAAEASKKPRQKRTATKAYNVTQAFGRRGPEQTQGNFGDQELIRQGTDYKHWPQIAQFAPSASAFFGMSRIGMEVTPSGTWLTYTGAIKLDDKDPNFKDQVILLNKHIDAYKTFPPTEPKKDKKKKADETQALPQRQKKQQTVTLLPAADLDDLSKQLQQSMSSADSTQA. “Carrier protein sequence”.

EpiVacCorona

Federal Budgetary Research Institution State Research Center of Virology and Biotechnology

peptide, russia

PATENT https://www.fips.ru/registers-doc-view/fips_servlet?DB=RUPAT&DocNumber=2743594&TypeFile=htmlRU 2 743 594 RU 2 743 593RU 2 743 595 RU 2 738 081 Science (Washington, DC, United States) (2021), 372(6538), 116-117. 

EpiVacCorona (Russian: ЭпиВакКорона, tr. EpiVakKorona) is a peptide-based vaccine against COVID-19 developed by the VECTOR center of Virology.[1][2][3] It consists of three chemically synthesized peptides (short fragments of a viral spike protein) that are conjugated to a large carrier protein. This protein is a fusion product of a viral nucleocapsid protein and a bacterial MBP protein.The third phase of a clinical trial, which should show whether the vaccine is able to protect people from COVID-19 or not, was launched in November 2020 with more than three thousand participants.[2] It is assumed it will be completed in August 2021.[2] According to the vaccine developers, the peptides and the viral part of the chimeric protein should immunize people who received this vaccine against SARS-CoV-2 and trigger the production of protective antibodies. However, some experts in the field have expressed concerns about the selection of peptides for use as vaccine antigens.[3][4] In addition, there are also serious concerns about the vaccine immunogenicity data, which have fueled independent civic research efforts[5][6][7] and criticism by some experts.[3][8][4][9][10] Meanwhile, the EpiVacCorona has received vaccine emergency authorization in a form of government registration and is available for vaccination outside the clinical trials.[11] The vaccine delivered via intramuscular route and aluminum hydroxide serves as an immunological adjuvant.

Description[edit]

Origin of EpiVacCorona antigenes

Composition

The vaccine includes three chemically synthesized short fragments of the viral spike protein – peptides, which, according to the developers of EpiVacCorona represent the protein regions containing B-cell epitopes that should be recognized by the human immune system.

These peptides are represented by following amino acid sequences:

1) CRLFRKSNLKPFERDISTEIYQAGS, 2) CKEIDRLNEVAKNLNESLIDLQE, 3) CKNLNESLIDLQELGKYEQYIK.[1][12][13]

In the vaccine all peptides are conjugated to a carrier protein, which is an expression product of the chimeric gene. This chimeric gene was created by fusion of two genes originating from different organisms, namely a gene encoding a viral nucleocapsid protein and a gene encoding a bacterial maltose-binding protein (MBP). The fusion chimeric gene expressed in Escherichia coli. The sequence of the chimeric protein is available from the patent.[4] The genetic construct of the chimeric gene also includes a short genetic fragment encoding a polyhistidine-tag, which is used to purify the chimeric protein from E. coli lysate. After the purification, the protein is conjugated with three peptides in a way that only one variant of the peptide molecule is attached to each protein molecule. As a result, three types of conjugated molecules are created: chimeric protein with attached peptide number 1, the same protein with peptide number 2, and finally the same protein with peptide number 3. All three types of conjugated molecules are included in the vaccine.[citation needed]

EpiVacCorona: antigens origin and composition

Vaccine antigens and antibodies

According to the developers’ publications,[14][5][6] vaccine antigens are three peptides of the spike protein and a chimeric protein consisting of two parts (viral nucleocapsid protein and bacterial maltose-binding protein). In addition, the polyhistidine-tag – a short peptide that is introduced into a vaccine composition to purify a chimeric protein from a bacterial lysate – is also a vaccine antigen against which antibodies can form in those who have received the vaccine. A person vaccinated with EpiVacCorona can develop antibodies not only to the peptides of the spike protein, but also to other antigens present in the vaccine. According to Anna Popova who is a head of the Federal Service for Supervision of Consumer Rights Protection and Human Welfare, it takes 42 days for those vaccinated with EpiVacCorona to develop immunity.[15]

figure2

Development

Immunogenic peptide screening in rabbits for EpiVacCorona design

Preclinical studies

The primary screening of peptides for the search for the most immunogenic ones was carried out in animals. The level of antibodies that was triggered by each tested peptide after administration to rabbits was measured. In the test, hemocyanin protein was used as a carrier protein for the studied peptides. Further, on six species of animals (mice, rats, rabbits, African green monkeys, rhesus monkeys, guinea pigs), the vaccine was shown to be harmless in terms of such parameters as general toxicity, allergic properties, and mutagenic activity. In four species of animals (hamsters, ferrets, African green monkeys, rhesus monkeys), specific activity was shown: immunogenicity and protective properties against SARS-CoV-2. The main results of preclinical studies are published in the “Bulletin of the Russian Academy of Medical Sciences”.[12][13]

Clinical studies

The studies development timeline was reported in Russian media in January 2021.[16] There are currently two clinical trials of EpiVacCorona registered in the ClinicalTrials.gov database.[17][18][2]

Phase I-II

The trial “Study of the Safety, Reactogenicity and Immunogenicity of “EpiVacCorona” Vaccine for the Prevention of COVID-19 (EpiVacCorona)”[18] was registered in clinical trial database with ClinicalTrials.gov identifier: NCT04780035. Another trial with the same title was registered with ClinicalTrials.gov Identifier: NCT04527575. Results of the trial that included data on 86 participants were published in Russian Journal of Infection and Immunity, indicating preliminary evidence of safety and an immune response.[1] The publication reports preliminary results of the first two phases of clinical trials of the vaccine in volunteers, of which 14 people aged 18-30 years participated in the first phase, and 86 volunteers aged 18-60 years in the second phase. It is claimed that antibodies were formed in 100% of the volunteers, and the vaccine is also claimed to be safe.[1]

EpiVacCorona Vaccine Development Timeline

Phase III

The third phase of a clinical trial, which should show whether the vaccine is able to protect people from COVID-19 or not, was launched in November 2020 with more than three thousand participants planned. It is expected to be completed in September 2021.[2] In the clinical trials database the phase III trial etitled “Study of the Tolerability, Safety, Immunogenicity and Preventive Efficacy of the EpiVacCorona Vaccine for the Prevention of COVID-19[2]” was registered only in March 2021 with ClinicalTrials.gov Identifier: NCT04780035. Phase 3-4 trial was registered in Russia at 18.11.2020 with 4991 participants planned.[19]

Intellectual property

The following patents of the Russian Federation for invention have been published, which protect the EpiVacCorona vaccine:

Peptide immunogens and vaccine composition against coronavirus infection COVID-19 using peptide immunogens” (No. 2738081). There are 7 peptides in patented vaccine compositions.

Peptide immunogens and vaccine composition against coronavirus infection COVID-19 using peptide immunogens” (No. 2743593). The patented vaccine composition contains 2 peptides.

Peptide immunogens used as a component of a vaccine composition against coronavirus infection COVID-19″ (No. 2743594). The patented vaccine composition contains 3 peptides.

Vaccine composition against coronavirus infection COVID-19″ (No. 2743595). The patented vaccine composition contains 3 peptides.

In all of these patents, the carrier protein is referred to as a chimeric fusion protein with an amino acid sequence derived from two parts, a bacterial maltose binding protein and a viral nucleocapsid protein.[20]

EpiVacCorona vaccine registration certificate

Authorization

 
  Full authorization  Emergency authorization

See also: List of COVID-19 vaccine authorizations § EpiVacCorona

The VECTOR has received vaccine emergency authorization in a form of government registration in October 2020.[21]

In Russia phase III clinical study is called post-registration study. Therefore, government registration of the vaccine means permission to perform phase III clinical research and public vaccination outside of clinical trials as well.[21] Since December 2020, the vaccine has been released for public vaccination in Russia.[22]

As of March 2021, Turkmenistan is the only foreign state to register EpiVacCorona with full authorization.[23][24]

Russia’s Chief Health Officer Anna Popova said: “In December 2020 the EpiVacCorona documents were presented to the World Health Organization, and we are expecting a decision from WHO.”[25] However, Deutsche Welle reports “As of March 1, the WHO had yet to receive an Expression of Interest (EOI) from EpiVacCorona’s developers, “VECTOR,” to enable WHO experts to evaluate their vaccine.”[26]

Export

The Deputy Director-General of the World Health Organization (WHO) Dr. Soumya Swaminathan during news conference in Geneva that took place in October 2020, told: “We will only be able to have a position on a vaccine when we see results of the phase III clinical trials.”[27] According to the center’s director Rinat Maksyutov, many government and non-government organizations want to test or be involved in the production of the vaccine.[28] As of March 30, Venezuela obtained 1000 doses of the Russian EpiVacCorona vaccine for a trial.[29] Venezuela also has reached a deal to purchase doses of the vaccine, as well as manufacture it locally, Vice President Delcy Rodriguez provided this information on June 4, 2021.[30] Turkmenistan expects to receive EpiVacCorona, as the vaccine has already been approved for use in that country.[31]

Controversy

Independent study of clinical trial participants

Ministry of Health’s response to a request from trial participants to perform independent antibody screening tests

English translation of Ministry of Health’s response to a request from trial participants to perform independent antibody screening tests.

At the start of the Phase III, trial participants and those vaccinated outside the trial began to form a community through the Telegram messenger network. On January 18, 2021, the members of the community turned to the Ministry of Health of the Russian Federation with an open letter, in which they stated that the production of antibodies after vaccination among them is much lower than declared by vaccine developers. Study participants claimed that antibodies were not found in more than 50% of those who documented their participation in the study, although only 25% of the participants should have had a placebo according to the study design. The trial participants also claimed that negative results were obtained using the a special ELISA test developed and recommended by VECTOR for EpiVacCorona detection.[5][6][4] More questions about the quality and protectiveness of antibodies induced by EpiVacCorona appeared along with the first results of a special antibody VECTOR’s test, when, with a positive special test, negative results of all other commercially available tests were otained: LIAISON SARS-CoV-2 S1 / S2 IgG – DiaSorin, IgM / IgG – Mindray, SARS-CoV-2 IgG – Abbott Architect, Anti-SARS-CoV-2 ELISA (IgG) – Euroimmun, Access SARS-CoV-2 IgG (RBD) – Beckman Coulter, “SARS-CoV-2-IgG-ELISA -BEST “-” Vector-Best “,” Anti-RBD IgG “- Gamaleya Research Center.[5][6][4][8] Clinical trial participants conducted their own antibody mini-study that was performed in independent Russian laboratory. The study participants asked Dr. Alexander Chepurnov, the former head of the infectious diseases department at VECTOR, who now works at another medical institute, to check neutralizing antibodies presence in their serum samples.[3] They also sent to Dr. Chepurnov control serum samples from former COVID-19 patients or people vaccinated with another Russian vaccine, Sputnik V, which is known to trigger the production of neutralizing antibodies.[32] All serum samples were blinded before antibody tests. On 23 March 2021, the participants reported the results of their mini-study in an open letter to the Ministry of Health of the Russian Federation.[6][7] According to the letter, even with the help of the VECTOR antibody detection system, antibodies were detected only in 70-75% of those vaccinated with EpiVacCorona. However, the level of antibodies was very low. Moreover, according to the letter, virus-neutralizing antibodies were not detected in the independent research Dr. Alexander Chepurnov laboratory at all.[3][6][7] The trial participants asked Ministry of Health in their open letter to perform independent study for the verification of their findings.[3][6][7] In addition, the letter reports 18 cases of COVID-19 cases as of March 22, 2021 among those who received the vaccine and became ill (sometimes severe) three weeks or later after the second dose of EpiVacCorona.[33][6][7] April 20, 2021 the study participants got a reply, with refusal of performing any additional verification antibody tests or investigation of sever COVID-19 cases among vaccinated individuals. The reply include the following text: “Considering that the listed immunobiological preparations (vaccines) for the prevention of COVID-19 are registered in the prescribed manner, their effectiveness and safety have been confirmed.”

Vaccine criticism by independent experts

Some independent experts criticized the vaccine design[3][4] and clinical data presentation in the publication.[8][9][10] The experts are saying that peptide selection is “crucial” for the innovative peptide approach, which VECTOR uses for EpiVacCorona design. However, some researchers are not convinced that the viral spike protein peptides selected for the vaccine are actually “visible” by human immune system.[3][4][34] They stated that these peptides do not overlap[35] with peptides that have been shown in several publications to contain human linear B cell epitopes in spike protein of SARS-CoV-2.[36][37][38][39][40] Moreover, the study was criticized for the lack of positive control of convalescent plasma samples in reports related to neutralizing antibody titers in vaccinated individuals.[1][10] The same study was also criticized for presence of detectable antibodies in negative controls samples that were not discussed by authors.[1][10] In addition, vaccine developers have been criticized for aggressively advertising their vaccine efficacy prior to the completion of phase III clinical trial. The most substantial criticism came from Dr. Konstantin Chumakov, who currently serves as the Associate Director for Research at the FDA Office of Vaccines Research and Review. Dr. Chumakov said: “I would not be in a hurry to call this peptide formulation a vaccine yet, because its effectiveness has not yet been proven…For the introduction of such a vaccine, the level of evidence must be much higher, and therefore the developers of EpiVacCorona, before launching their vaccine on the market, had to conduct clinical trials and prove that their vaccine actually protects against the disease. However, such tests were not carried out, which is absolutely unacceptable.”[41]

The title page of the “EpiVacCorona” patent with Anna’s Popova name among inventors

Conflict of interest

The vaccine design was protected by several already issued patents (see section above). In each patent one of its co-authors is a namesake of Anna Popova who is a head of the Federal Service for Supervision of Consumer Rights Protection and Human Welfare. This patent authorship represents an issue as far as Anna Popova is a head of the Russian agency that is charged with overseeing vaccine safety and efficacy. As a co-author of these patents, she might have an interest in promoting the vaccine despite its shortcomings.

References

  1. Jump up to:a b c d e f Ryzhikov AB, Ryzhikov EA, Bogryantseva MP, Usova SV, Danilenko ED, Nechaeva EA, Pyankov OV, Pyankova OG, Gudymo AS, Bodnev SA, Onkhonova GS, Sleptsova ES, Kuzubov VI, Ryndyuk NN, Ginko ZI, Petrov VN, Moiseeva AA, Torzhkova PY, Pyankov SA, Tregubchak TV, Antonec DV, Gavrilova EV, Maksyutov RA (2021). “A single blind, placebo-controlled randomized study of the safety, reactogenicity and immunogenicity of the “EpiVacCorona” Vaccine for the prevention of COVID-19, in volunteers aged 18–60 years (phase I–II)”Russian Journal of Infection and Immunity11 (2): 283–296. doi:10.15789/2220-7619-ASB-1699.
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  34. ^ Li, Yang; Ma, Ming-Liang; Lei, Qing; Wang, Feng; Hong, Wei; Lai, Dan-Yun; Hou, Hongyan; Xu, Zhao-Wei; Zhang, Bo; Chen, Hong; Yu, Caizheng (30 March 2021). “Linear epitope landscape of the SARS-CoV-2 Spike protein constructed from 1,051 COVID-19 patients”Cell Reports34 (13): 108915. doi:10.1016/j.celrep.2021.108915ISSN 2211-1247PMC 7953450PMID 33761319.
  35. ^ “Вакцина “ЭпиВакКорона” в иллюстрациях”Троицкий вариант — Наука (in Russian). 23 March 2021. Retrieved 24 April 2021.
  36. ^ Yi, Zhigang; Ling, Yun; Zhang, Xiaonan; Chen, Jieliang; Hu, Kongying; Wang, Yuyan; Song, Wuhui; Ying, Tianlei; Zhang, Rong; Lu, HongZhou; Yuan, Zhenghong (December 2020). “Functional mapping of B-cell linear epitopes of SARS-CoV-2 in COVID-19 convalescent population”Emerging Microbes & Infections9 (1): 1988–1996. doi:10.1080/22221751.2020.1815591ISSN 2222-1751PMC 7534331PMID 32844713.
  37. ^ Poh, Chek Meng; Carissimo, Guillaume; Wang, Bei; Amrun, Siti Naqiah; Lee, Cheryl Yi-Pin; Chee, Rhonda Sin-Ling; Fong, Siew-Wai; Yeo, Nicholas Kim-Wah; Lee, Wen-Hsin; Torres-Ruesta, Anthony; Leo, Yee-Sin (1 June 2020). “Two linear epitopes on the SARS-CoV-2 spike protein that elicit neutralising antibodies in COVID-19 patients”Nature Communications11 (1): 2806. doi:10.1038/s41467-020-16638-2ISSN 2041-1723PMC 7264175PMID 32483236.
  38. ^ Li, Yang; Lai, Dan-Yun; Zhang, Hai-Nan; Jiang, He-Wei; Tian, Xiaolong; Ma, Ming-Liang; Qi, Huan; Meng, Qing-Feng; Guo, Shu-Juan; Wu, Yanling; Wang, Wei (October 2020). “Linear epitopes of SARS-CoV-2 spike protein elicit neutralizing antibodies in COVID-19 patients”Cellular & Molecular Immunology17 (10): 1095–1097. doi:10.1038/s41423-020-00523-5ISSN 2042-0226PMC 7475724PMID 32895485.
  39. ^ Farrera-Soler, Lluc; Daguer, Jean-Pierre; Barluenga, Sofia; Vadas, Oscar; Cohen, Patrick; Pagano, Sabrina; Yerly, Sabine; Kaiser, Laurent; Vuilleumier, Nicolas; Winssinger, Nicolas (2020). “Identification of immunodominant linear epitopes from SARS-CoV-2 patient plasma”PLOS ONE15 (9): e0238089. doi:10.1371/journal.pone.0238089ISSN 1932-6203PMC 7480855PMID 32903266.
  40. ^ Shrock, Ellen; Fujimura, Eric; Kula, Tomasz; Timms, Richard T.; Lee, I.-Hsiu; Leng, Yumei; Robinson, Matthew L.; Sie, Brandon M.; Li, Mamie Z.; Chen, Yuezhou; Logue, Jennifer (27 November 2020). “Viral epitope profiling of COVID-19 patients reveals cross-reactivity and correlates of severity”Science370 (6520): eabd4250. doi:10.1126/science.abd4250ISSN 1095-9203PMC 7857405PMID 32994364.
  41. ^ “Константин Чумаков: “Даже если человек переболел COVID-19, ему все равно нужно привиться. Иммунный ответ на прививку лучше и долговечнее, чем на саму болезнь””republic.ru (in Russian). Retrieved 24 April 2021.

External links

EpiVacCorona vaccine
Vaccine description
TargetSARS-CoV-2
Vaccine typePeptide subunit
Clinical data
Trade namesEpiVacCorona
Routes of
administration
Intramuscular
ATC codeNone
Legal status
Legal statusRegistered in Russia on 14 October 2020 RU Registered.TU approved.Full list : List of EpiVacCorona COVID-19 vaccine authorizations
Identifiers
DrugBankDB16439
Part of a series on the
COVID-19 pandemic
COVID-19 (disease)SARS-CoV-2 (virus)
showTimeline
showLocations
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showMedical response
showImpact
 COVID-19 portal

EpiVacCorona Vaccine, developed by the Vektor State Research Center of Virology and Biotechnology in Russia, is based on peptide-antigens that facilitate immunity to the SARS-CoV-2 virus1. It is currently being tested in Phase I/II clinical trials for safety and immunogenicity (NCT04527575)1,2.

  1. Precision Vaccinations: VACCINE INFO EpiVacCorona Vaccine [Link]
  2. The Pharma Letter: Russia’s EpiVacCorona vaccine post-registration trials started [Link]

//////EpiVacCorona, SARS-CoV-2, RUSSIA, CORONA VIRUS, COVID 19, VACCINE, PEPTIDE

wdt-16

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ZF2001, ZIFIVAX


Republic of Uzbekistan
Oʻzbekiston Respublikasi  (Uzbek)
FlagState emblem

ZF2001

ZIFIVAX

CAS 2609662-31-7 

A COVID-19 vaccine comprising a dimeric form of SARS-CoV-2 receptor-binding domain (RBD) produced in China hamster ovary (CHO) cells and adjuvanted with aluminum hydroxide (Anhui Zhifei Longcom/Institute of Microbiol. China Academy of Sciences)

Recombinant vaccine

Anhui Zhifei Longcom Biopharmaceutical, Institute of Microbiology of the Chinese Academy of Sciences

China, Uzbekistan

CHO Cells Recombinant Vaccine

  • ZF-2001
  • ZF-UZ-VAC2001
  • Chinese Academy of Sciences (Originator)
  • Zhifei Longcom (Originator)

Human SARS-CoV-2 (Covid-19 coronavirus) vaccine consisting of recombinant dimer comprising two RBD domains (R319-K527) of the spike glycoprotein of SARS-CoV-2 fused via a disulfide link; expressed in CHO cells

ZF-2001 is a recombinant coronavirus vaccine jointly developed by the Institute of Microbiology of the Chinese Academy of Sciences and Zhifei Longcom. The vaccine became available in 2021 in Uzbekistan under an emergency use authorization for the prevention of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (COVID-19). The vaccine is currently evaluated in phase III clinical trials.

This vaccine candidate, developed in China, uses SARS-CoV-2 protein subunits that are entirely engineered, created, and secreted by Chinese Hamster Ovary (CHO) cells1. The vaccine candidate is sponsored by Anhui Zhifei Longcom Biologic Pharmacy Co., Ltd. and is undergoing phase I clinical trials to evaluate safety and tolerability.

ZF2001, trade-named ZIFIVAX, is an adjuvanted protein subunit COVID-19 vaccine developed by Anhui Zhifei Longcom in collaboration with the Institute of Microbiology at the Chinese Academy of Sciences.[1][2] As of December 2020, the vaccine candidate was in Phase III trials with 29,000 participants in ChinaEcuadorMalaysiaPakistan, and Uzbekistan.[3][4]

ZF2001 employs technology similar to other protein-based vaccines in Phase III trials from NovavaxVector Institute, and Medicago.[5] It is administered in 3 doses over a period of 2 months.[6]

ZF2001 was first approved for use in Uzbekistan and later China.[7][8] Production capacity is expected to be one billion doses a year.[6] Phase II results published in The Lancet on the three dose administration showed seroconversion rates of neutralizing antibodies of between 92% to 97%.[9]

Anhui Zhifei Longcom Biopharmaceuticals began a phase 3 clinical trial for its recombinant protein vaccine candidate in December, according to the WHO. State-run China Global Television Network in November reported that a one-year trial would take place in Uzbekistan and aim to recruit 5,000 volunteers. Anhui Zhifei is a unit of private firm Chongqing Zhifei Biological Products. It is co-developing the vaccine with the Chinese Academy of Sciences, a government institution.

Emergency Use Authorization received in UZ by Zhifei Longcom for the prevention of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (COVID-19)

Description

As described in Cell, the CoV spike receptor-binding domain (RBD) is an attractive vaccine target for coronaviruses but is constrained by limited immunogenicity, however a dimeric form of MERS-CoV RBD offers greater protection. The RBD-dimer significantly increases neutralizing antibodies compared to a conventional monomeric form and protected mice against MERS-CoV infection. CoV RBD-dimer have been produced at high yields in pilot scale production.[10]

Rather than injecting a whole virus, subunit vaccines contains virus particles specially selected to stimulate an immune response. Because the fragments are incapable of causing disease, subunit vaccines are considered very safe.[11] Subunit vaccines in widespread use include the Hepatitis B vaccine and Pertussis vaccine. However, as only a few viral components are included in the vaccine which does not display the full complexity of the virus, their efficacy may be limited.[12] Subunit vaccines are delivered alongside adjuvants and booster doses may be required.[11]

According to industry experts, production for this kind of vaccine is stable and reliable, and easier to achieve large-scale industrial production at home and overseas. However it was noted it can be very inconvenient for people to come back for a second and third dose.[6]

figure2

ZF2001 (Anhui Zhifei Longcom Biopharmaceutical/Chinese Academy of Medical Sciences)

The latest subunit vaccine candidate to enter Phase 3 clinical studies is the adjuvanted RBD-dimeric antigen designed by Anhui Zhifei Longcom Biopharmaceutical and the Institute of Microbiology of the Chinese Academy of Medical Sciences. Phase 3 clinical study was launched on December104 and will be initially carried out in China and Uzbekistan while Indonesia, Pakistan and Ecuador will follow as study sites (Clinical Trial Identifier: NCT04646590 and Registration Number: ChiCTR2000040153). The design of the study involves recruitment of 22,000 volunteers from China and 7000 subjects outside China for a total of 29,000 volunteers. There are still no published results on this candidate, however data from its Phase 2 placebo-controlled clinical trial (Clinical Trial Identifier: NCT04466085) conducted on a total of 900 participants ranging from 18 to 59 years old suggest that a 2 or 3 dose regimen is evaluated. Each immunization will be separated by the next by 4 weeks.

Development

Phase I and II trials and results

In June, Longcom began a double-blind, randomized, placebo parallel controlled Phase I trial with 50 participants aged 18–59 in Chongqing divided into low-dose, high-dose, and placebo groups.[13]

In July, Longcom began a randomized, double-blind, placebo-controlled Phase II trial with 900 participants aged 18–59 in ChangshaHunan divided into low-dose, high-dose, and placebo groups.[14] In August, an additional Phase II trial was launched with 50 participants aged 60 and above.[15][1]

In Phase II results published in The Lancet, on the two-dose schedule, seroconversion rates of neutralizing antibodies after the second dose were 76% (114 of 150 participants) in a 25 μg group and 72% (108 of 150) in a 50 μg group. On the three-dose schedule, seroconversion rate of neutralizing antibodies after the third dose were 97% (143 of 148 participants) in the 25 μg group and 93% (138 of 148) in the 50 μg group. 7 to 14 days after the administration of the third dose, the GMTs of neutralizing antibodies reached levels that were significantly higher than observed in human convalescent serum of recovering COVID-19 patients, especially in the 25 μg group.[9]

Phase III trials

In December, Longcom began enrollment of a Phase III randomized, double-blind, placebo-controlled clinical trial for 29,000 participants, including 750 participants between 18-59 and 250 participants 60 and older in China and 21,000 participants between 18-59 and 7,000 participants 60 and older outside China.[16][17]

In December, Malaysia‘s MyEG announced it would conduct Phase III trials. If the trials were successful, MyEG would be the sole distributor of ZF2001 in Malaysia for 3 years.[4]

In December, Uzbekistan began a year-long Phase III trial of ZF2001 with 5,000 volunteers between 18 and 59.[18][19]

In December, Ecuador‘s Minister of Health, Juan Carlos Zevallos announced Phase III trials would involve between 5,000 and 8,000 volunteers.[20]

In February, Pakistan‘s Drug Regulatory Authority (DRAP) approved Phase III trials with approximately 10,000 participants to be conducted at UHS Lahore, National Defense Hospital, and Agha Khan Hospital.[21]

Discussions to begin Phase III trials are also underway in Indonesia.[17][22]

COVID-19 Variants

In February, lab studies of twelve serum samples taken from recipients of BBIBP-CorV and ZF2001 retained neutralizing activity against the Beta variant although with weaker activity than against the original virus.[23] For ZF-2001, geometric mean titers declined by 1.6-fold, from 106.1 to 66.6, which was less than antisera from mRNA vaccine recipients with a 6-folds decrease.[24] Preliminary clinical data from Novavax and Johnson & Johnson also showed they were less effective in preventing COVID-19 in South Africa, where the new variant is widespread.[23]

Manufacturing

The company’s vaccine manufacturing facility was put into use in September.[17] In February 2021, Pu Jiang, General Manager of Zhifei Longcom, said the company had an annual production capacity of 1 billion doses.[6]

Marketing and deployment

 
  Full authorization  Emergency authorization

See also: List of COVID-19 vaccine authorizations § RBD-Dimer

On March 1, Uzbekistan granted approval for ZF2001 (under tradename ZF-UZ-VAC 2001) after having taken part in the Phase III trials.[8] In March, Uzbekistan received 1 million doses and started vaccinations in April.[25] By May, a total of 3 million doses had been delivered.[26]

On March 15, China approve of ZF2001 for emergency use after being approved by Uzbekistan earlier in the month.[7]

References

  1. Jump up to:a b “Anhui Zhifei Longcom: RBD-Dimer – COVID19 Vaccine Tracker”covid19.trackvaccines.org. Retrieved 27 December2020.
  2. ^ “COVID-19 Vaccine: ZIFIVAX by Anhui Zhifei Longcom Biopharma, Institute of Microbiology Chinese Academy of Sciences”covidvax.org. Retrieved 27 December 2020.
  3. ^ “Fifth Chinese Covid-19 vaccine candidate ready to enter phase 3 trials”South China Morning Post. 20 November 2020. Retrieved 27 December 2020.
  4. Jump up to:a b Ying TP (7 December 2020). “MYEG to conduct phase 3 clinical trial for China’s Covid-19 vaccine in Msia | New Straits Times”NST Online. Retrieved 27 December 2020.
  5. ^ Zimmer C, Corum J, Wee SL (10 June 2020). “Coronavirus Vaccine Tracker”The New York TimesISSN 0362-4331. Retrieved 27 December 2020.
  6. Jump up to:a b c d “China’s production bottleneck ‘could be eased with latest Covid-19 vaccine'”South China Morning Post. 17 March 2021. Retrieved 18 March 2021.
  7. Jump up to:a b Liu, Roxanne (15 March 2021). “China IMCAS’s COVID-19 vaccine obtained emergency use approval in China”Reuters. Retrieved 15 March 2021.
  8. Jump up to:a b Mamatkulov, Mukhammadsharif (1 March 2021). “Uzbekistan approves Chinese-developed COVID-19 vaccine”Reuters. Retrieved 2 March 2021.
  9. Jump up to:a b Yang, Shilong; Li, Yan; Dai, Lianpan; Wang, Jianfeng; He, Peng; Li, Changgui; Fang, Xin; Wang, Chenfei; Zhao, Xiang; Huang, Enqi; Wu, Changwei (24 March 2021). “Safety and immunogenicity of a recombinant tandem-repeat dimeric RBD-based protein subunit vaccine (ZF2001) against COVID-19 in adults: two randomised, double-blind, placebo-controlled, phase 1 and 2 trials”The Lancet Infectious Diseases0doi:10.1016/S1473-3099(21)00127-4ISSN 1473-3099PMC 7990482PMID 33773111.
  10. ^ Dai L, Zheng T, Xu K, Han Y, Xu L, Huang E, et al. (August 2020). “A Universal Design of Betacoronavirus Vaccines against COVID-19, MERS, and SARS”Cell182 (3): 722–733.e11. doi:10.1016/j.cell.2020.06.035PMC 7321023PMID 32645327.
  11. Jump up to:a b “What are protein subunit vaccines and how could they be used against COVID-19?”http://www.gavi.org. Retrieved 27 December2020.
  12. ^ Dong Y, Dai T, Wei Y, Zhang L, Zheng M, Zhou F (October 2020). “A systematic review of SARS-CoV-2 vaccine candidates”Signal Transduction and Targeted Therapy5 (1): 237. doi:10.1038/s41392-020-00352-yPMC 7551521PMID 33051445.
  13. ^ Clinical trial number NCT04445194 for “Phase I Clinical Study of Recombinant Novel Coronavirus Vaccine” at ClinicalTrials.gov
  14. ^ Clinical trial number NCT04466085 for “A Randomized, Blinded, Placebo-controlled Trial to Evaluate the Immunogenicity and Safety of a Recombinant New Coronavirus Vaccine (CHO Cell) With Different Doses and Different Immunization Procedures in Healthy People Aged 18 to 59 Years” at ClinicalTrials.gov
  15. ^ Clinical trial number NCT04550351 for “A Randomized, Double-blind, Placebo-controlled Phase I Clinical Trial to Evaluate the Safety and Tolerability of Recombinant New Coronavirus Vaccines (CHO Cells) in Healthy People Aged 60 Years and Above” at ClinicalTrials.gov
  16. ^ Clinical trial number NCT04646590 for “A Phase III Randomized, Double-blind, Placebo-controlled Clinical Trial in 18 Years of Age and Above to Determine the Safety and Efficacy of ZF2001, a Recombinant Novel Coronavirus Vaccine (CHO Cell) for Prevention of COVID-19” at ClinicalTrials.gov
  17. Jump up to:a b c “Another Chinese Covid-19 vaccine enters late-stage human trials with a plan to produce 300 million doses annually”Business Insider. Retrieved 27 December 2020.
  18. ^ Reuters Staff (11 November 2020). “Uzbekistan to carry out late-stage trial of Chinese COVID-19 vaccine candidate”Reuters. Retrieved 27 December 2020.
  19. ^ “Uzbekistan poised to start trials on Chinese COVID-19 vaccine | Eurasianet”eurasianet.org. Retrieved 27 December 2020.
  20. ^ “Ecuador participará en ensayos de una vacuna china contra el covid-19”CNN (in Spanish). 29 December 2020. Retrieved 23 January 2021.
  21. ^ “China’s third vaccine enters Pakistan”The Nation. 15 February 2021. Retrieved 28 February 2021.
  22. ^ “Covid vaccine tracker: How do the leading jabs compare?”http://www.ft.com. 23 December 2020. Retrieved 27 December 2020.
  23. Jump up to:a b Liu, Roxanne (3 February 2021). “Sinopharm’s COVID-19 vaccine remained active against S.Africa variant, effect reduced – lab study”Reuters. Retrieved 29 March 2021.
  24. ^ Huang, Baoying; Dai, Lianpan; Wang, Hui; Hu, Zhongyu; Yang, Xiaoming; Tan, Wenjie; Gao, George F. (2 February 2021). “Neutralization of SARS-CoV-2 VOC 501Y.V2 by human antisera elicited by both inactivated BBIBP-CorV and recombinant dimeric RBD ZF2001 vaccines”bioRxiv: 2021.02.01.429069. doi:10.1101/2021.02.01.429069.
  25. ^ uz, Kun. “Uzbekistan receives 1 million doses of ZF-UZ-VAC 2001 vaccine”Kun.uz. Retrieved 28 March 2021.
  26. ^ Romakayeva, Klavdiya (18 May 2021). “Uzbekistan receives third batch of Chinese-Uzbek COVID-19 vaccine”Trend.Az. Retrieved 19 May 2021.

 

Vaccine description
TargetSARS-CoV-2
Vaccine typeProtein subunit
Clinical data
Trade namesZIFIVAX
Routes of
administration
Intramuscular
ATC codeNone
Identifiers
DrugBankDB15893
Part of a series on the
COVID-19 pandemic
COVID-19 (disease)SARS-CoV-2 (virus)
showTimeline
showLocations
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////////ZF2001, ZIFIVAX, corona virus, covid 19, SARS-CoV-2ZF 2001, ZF-UZ-VAC2001, Uzbekistan, approvals 2021

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Estetrol


Skeletal formula of estetrol
Estetrol (USAN).png

Estetrol

エステトロール;

FormulaC18H24O4
CAS15183-37-6
Mol weight304.3808

FDA 4/15/2021, To prevent pregnancy, Nextstellis

New Drug Application (NDA): 214154
Company: MAYNE PHARMA

Label (PDF)
Letter (PDF)
Review

Label (PDF)

PATENT

https://patents.google.com/patent/EP1562976B1/en

Estrogenic substances are commonly used in methods of Hormone Replacement Therapy (HRT) and methods of female contraception. These estrogenic substances can be divided in natural estrogens and synthetic estrogens. Examples of natural estrogens that have found pharmaceutical application include estradiol, estrone, estriol and conjugated equine estrogens. Examples of synthetic estrogens, which offer the advantage of high oral bioavailability include ethinyl estradiol and mestranol.Recently, estetrol has been found effective as an estrogenic substance for use in HRT, disclosure of which is given in the Applicant’s co-pending application WO 02/094276 . Estetrol is a biogenic estrogen that is endogeneously produced by the fetal liver during human pregnancy. Other important applications of estetrol are in the fields of contraception, therapy of auto-immune diseases, prevention and therapy of breast and colon tumors, enhancement of libido, skin care, and wound healing as described in the Applicant’s co-pending applications WO 02/094276 , WO 02/094279 , WO 02/094278 , WO 02/094275 , EP 1511496 A1 EP 1511498 A1 , WO 03/041718 , WO 03/018026 , EP 1526856 A1 and WO 04/0278032 .[0004]The synthesis of estetrol and derivatives thereof on a laboratory scale basis is known in the art: Fishman J., Guzik H., J. Org. Chem. 33, 3133 – 3135 (1968); Nambara T. et al., Steroids 27, 111 – 121 (1976); or Suzuki E. et al., Steroids 60, 277 – 284(1995).[0005]

Fishman J., Guzik H., J. Org. Chem. 33, 3133 – 3135 (1968) discloses a successful synthesis of estetrol from an estrone derivative (compound (III); cf. for a synthesis of compound (III) Cantrall, E.W., Littell, R., Bernstein, S. J. Org. Chem 29, 214 – 217 (1964)). In a first step, the carbonyl group at C17 of compound (III) was reduced with LiAlH4 to estra-1,3,5(10),15-tetraene-3,17-diol (compound VIa) that was isolated as the diacetate (compound VIb). Compound VIb was subjected to cis-hydroxylation of the double bond of ring D by using OsO4 which resulted into the formation of estra-1,3,5(10)-triene-3,15α,16α,17β-tetraol-3,17-diacetate (compound Ib) that under heating with K2CO3 in methanol produces estetrol (Scheme 1).

Figure imgb0001

[0006]

The overall yield of this three step process is, starting from estrone derivative III, only about 7%. It is worth noting that the protected derivative 17,17-ethylenedioxyestra-1,3,5(10),15-tetraene-3-ol-3-acetate (compound IV) could be cis-hydroxylated to its 15α,16α-diol derivative (compound Va), but that thereafter the dioxolane group could not be removed (p-toluene sulfonic acid in acetone at room temperature) or that the hydrolysis (aqueous sulfuric acid in warm dioxane) of the dioxolane group resulted in a mixture containing a multitude of products (Scheme 2).

Figure imgb0002

[0007]Nambara T. et al., Steroids 27, 111 – 121 (1976) discloses another synthesis of estetrol wherein estrone is the starting material. The carbonyl group of estrone is first protected by treatment with ethylene glycol and pyridine hydrochloride followed by acetylation of the hydroxy group at C3. The next sequence of steps involved a bromination/base catalyzed dehydrobromination resulting into the formation of 17,17-ethylenedioxyestra-1,3,5(10),15-tetraene-3-ol (compound IVa). This compound IVa was subsequently acetylated which produced 17,17-ethylenedioxyestra-1,3,5(10),15-tetraene-3-ol-3-acetate (compound IVb). In a next step, the dioxolane group of compound IVb was hydrolysed by using p-toluene sulfonic acid to compound Vb, followed subsequently by reduction of the carbonyl group at C17 (compound Vc) and oxidation of the double bond of ring D thereby forming estra-1,3,5(10)-triene-3,15α,16α,17β-tetraol-3,17-diacetate (compound VIb). See Scheme 3.[0008]

Suzuki E. et al., Steroids 60, 277 – 284 (1995) also discloses the synthesis of estetrol by using compound Vb of Nambara T. et al. as starting material. The carbonyl group at C17 of this compound was first reduced followed by acetylation yielding estra-1,3,5(10),15-tetraene-3,17-diol-3,17-diacetate (compound 2b). The latter was subjected to oxidation with OsO4 which provided estra-1,3,5(10)-triene-3,15α,16α,17β-tetraol-3,17-diacetate (compound 3b) in 46% yield.

Figure imgb0003

[0009]According to the Nambara T. et al. and Suzuki E. et al., the synthesis of estetrol can be performed with a yield of approximately 8%, starting from estrone.0010]

Poirier D., et al., Tetrahedron 47, 7751 – 7766 (1991) discloses the following compounds which were prepared according to methods that have been used to prepare similar compounds:

Figure imgb0004

[0011]Dionne, P. et al., Steriods 62, 674 – 681 (1997) discloses the compound shown above wherein R is either methyl or t-butyldimethylsilyl.[0012]Magnus, P. et al., J. Am. Chem. Soc. 120, 12486 -12499 (1998) discloses that the main methods for the synthesis of α,β-unsaturated ketones from saturated ketones are (a) halogenation followed by dehydrohalogenation, (b) utilising sulphur or selenium derivatives, (c) DDQ and (d) utilizing palladium(II) complexes.[0013]Furthermore, it has also been found that by following the prior art methods mentioned above, estetrol of high purity was obtained only in low yield when using an acetyl group as a protecting group for the 3-hydroxy group of estra-1,3,5(10),15-tetraen-3-ol-17-one, in particular because its sensitivity to hydrolysis and solvolysis. In particular, the lability of the acetyl group lead not only to an increased formation of byproducts during the reactions, but also during chromatography and crystallisation for purification of intermediate products when protic solvents such as methanol were used. Therefore, it is difficult to isolate purified estetrol and intermediates thereof in good yield.

Example 7 3-Benzyloxy-estra-1,3,5 (10),15-tetraen-17-ol (compound 5; A = benzyl)

[0088]To a solution of 3-benzyl-dehydroestrone (compound 6; A = benzyl; 58 g, 162 mmol) in a mixture of MeOH (900 mL) and THF (200 mL) at room temperature was added CeCl3 heptahydrate (66.4 g, 178 mmol). After stirring for 1 h the mixture was cooled to 0-5°C using an ice/water bath. Then NaBH4 (12.2 g, 324 mmol) was added in small portions maintaining a temperature below 8°C. After stirring for 2 h at 0-5°C (TLC showed the reaction to be complete) 1 N NaOH (300 mL) and DCM (1 L) were added and the mixture was stirred for ½ h at room temperature. The layers were separated and the aqueous layer was extracted with DCM (200 mL). The organic layers were combined, dried (Na2SO4) and concentrated in vacuo to give an off-white solid (55.0 g, 152.8 mmol, 94%) TLC: Rf = 0.25 (heptanes/ethyl acetate = 4:1); HPLC-MS: 93% β-isomer, 2% α-isomer; DSC: Mp. 149.7°C, purity 96.6%; 1H-NMR (200 MHz, CDCl3) δ 7.48 (m, 5H), 7.27 (d, 1H, J = 8.4 Hz), 6.85 (dd, 1H, J1 = 2.8 Hz, J2 = 8.6 Hz), 6.81 (d, 1H, J = 2.4 Hz), 6.10 (d, 1H, J = 5.8 Hz), 5.79 (dd, 1H, J1 = 1.8 Hz, J2 = 3.4 Hz), 5.11 (s, 2H), 4.48 (d, 1H, J = 7.6), 2.96 (m, 2H), 2.46 – 1.64 (m, 9H), 0.93 (s, 3H) ppm.

Example 8 17-Acetyloxy-3-benzyloxy-estra-1,3,5 (10),15-tetraene (compound 4; A = benzyl, C = acetyl)

[0089]A solution of 3-Benzyloxy-estra-1,3,5 (10),15-tetraen-17-ol (compound 5; A = benzyl; 55.0 g, max. 153 mmol) in pyridine (400 mL) was treated with Ac2O (50 mL, 0.53 mol) and 4-dimethylaminopyridine (1.5 g, 12.3 mmol). The mixture was stirred for 2 h at room temperature (TLC showed the reaction to be complete). It was concentrated in vacuo. The residue was dissolved in EtOAc (400 mL), washed with water (200 mL) and brine (150 mL), dried (Na2SO4) and concentrated in vacuo to yield a yellow solid (54.0 g, 49.8 mmol, 88%). The product was purified by recrystallization from heptanes/ EtOAc/ EtOH (1:0.5:1) to afford a white solid (45.0 g, 112 mmol, 73%) TLC: Rf = 0.6 (heptanes/ethyl acetate = 4/1); HPLC-MS: 98% β-isomer, 1% α-isomer, 1.3% ß-estradiol; DSC: Mp. 122.8°C, purity 99.8%; 1H-NMR (200 MHz, CDCl3) δ 7.44 (m, 5H), 7.27 (d, 1H, J = 8.4 Hz), 6.86 (dd, 1H, J1 = 2.6 Hz, J2 = 8.4 Hz), 6.80 (d, 1H, J = 2.6 Hz), 6.17 (d, 1H, J = 5.8 Hz), 5.78 (dd, 1H, J1 = 1.4 Hz, J2 = 3.2 Hz), 5.45 (m, 1H), 5.11 (s, 2H), 2.96 (m, 2H), 2.40 – 1.54 (m, 10H), 2.18 (s, 3H), 0.93 (s, 3H) ppm.

Example 9 17-Acetyl-3-Benzyl estetrol (compound 3; A = benzyl, C = acetyl)

[0090]OsO4 on PVP (9 g, ~5% w/w OsO4 on PVP, prepared according to Cainelli et al. Synthesis, 45 – 47 (1989) was added to a solution of 17-Acetyloxy-3-benzyloxy-estra-1,3,5 (10),15-tetraene (compound 4; A = benzyl, C = acetyl; 45 g, 112 mmol) in THF (450 mL) and the mixture was heated to 50°C. Trimethylamine-N-oxide dihydrate (24.9 g, 224 mmol) was added portion-wise over 2 h. After stirring for 36 h at 50°C (TLC showed the reaction to be complete) the reaction mixture was cooled to room temperature. The solids were filtered off, washed with THF (100 mL) and the filtrate was concentrated. The residue was taken up in EtOAc (250 mL) and water (250 mL) was added. The aqueous layer was acidified with 1 N HCl (ca. 10 mL). The layers were separated and the aqueous layer was extracted with EtOAc (150 mL). The organic layers were combined, dried (Na2SO4) and concentrated in vacuo. The residue was triturated with heptanes/EtOAc (1:1, 100 mL), stirred for 2 h and the resulting white precipitate was filtered off to give the product as a white solid (41 g, 94 mmol, 84%). The product was purified by recrystallization from heptanes/ ethyl acetate/ EtOH (2:1:1) three times to afford a white solid (21 g, 48.2 mmol, 43%). HPLC-MS: 99.5% βαα-isomer; DSC: Mp. 159.3°C, purity 98.7%; 1H-NMR (200 MHz, CDCl3) δ 7.49 (m, 5H), 7.27 (d, 1H, J = 8.4 Hz), 6.84 (dd, 1H, J1 = 2.6 Hz, J2 = 8.4 Hz), 6.81 (d, 1H, J = 2.4 Hz), 5.11 (s, 2H), 4.45 (d, 1H, J = 4.4), 4.11 (m, 3H), 3.12 (m, 1H) 2.95 (m, 2H), 2.46 -1.64 (m, 10H), 2.24 (s, 3H), 0.93 (s, 3H) ppm.

Example 10 17-Acetyl estetrol (compound 2; C = acetyl)

[0091]To a solution of 17-acetyl-3-benzyl estetrol (compound 3; A = benzyl, C = acetyl; 21 g, 48.2 mmol) in MeOH (600 mL, HPLC-grade) was added a preformed suspension of 10% Palladium on activated carbon (2 g) in methanol (50 mL). The mixture was placed under an atmosphere of H2 at 1 atm and stirred for 24 h (TLC showed the reaction to be completed) at room temperature. It was filtered over Celite® and the filter cake was washed with MeOH (200 mL). The filtrate was concentrated in vacuo to give 17-acetyl estetrol as a white solid (15 g, 43.4 mmol, 90%). TLC: Rf = 0.2 (heptanes/ethyl acetate = 1/1); HPLC-MS: 99.2%, DSC: Mp. 212.2°C, purity 98.9%; 1H-NMR (200 MHz, CD3OD) δ 7.14 (d, 1H, J = 8.0 Hz), 6.60 (dd, 1H, J1 = 2.6 Hz, J2 = 8.8 Hz), 6.56 (d, 1H, J = 2.4 Hz), 4.81 (dd, 1H, J1 = 3.4 Hz, J2 = 6.4 Hz), 4.07 (m, 3H), 3.12 (m, 1H), 2.85 (m, 2H), 2.37 – 1.37 (m, 10H), 2.18 (s, 3H), 0.91 (s, 3H) ppm.

Example 11 Estetrol

[0092]17-Acetyl-estetrol (compound 2; C = acetyl; 15 g, 43.4 mmol) and K2CO3 (6 g, 43.4 mmol) were suspended in MeOH (500 mL, HPLC-grade) and stirred for 4 h at room temperature (TLC showed the reaction to be complete). The solvents were evaporated in vacuo. Water (200 mL) and CHCl3 (70 mL) were added and the mixture was stirred and neutralized with 0.1 N HCl (50 mL). The product was collected by filtration, washed with water (100 mL) and CHCl3 (100 mL) to give estetrol as a white solid (12.2 g, 40.1 mmol, 92.5%, overall yield from estrone 10.8%) after drying at 40°C in an air-ventilated oven. TLC: Rf = 0.05 (heptanes/ethyl acetate = 1/1); HPLC-MS: 99.1%, DSC: Mp. 243.7°C, purity 99.5%; 1H-NMR (200 MHz, CD3OD) δ 7.14 (d, 1H, J = 8.6 Hz), 6.61 (dd, 1H, J1 = 2.6 Hz, J2 = 8.4 Hz), 6.56 (d, 1H, J = 2.4 Hz), 4.83 (m, 1H), 3.93 (m, 3H), 3.50 (d, 1H, J = 5.2), 3.38 (m, 2H), 2.84 (m, 2H), 2.32 (m, 3H), 1.97 (m, 1H), 1.68 – 1.24 (m, 5H), 0.86 (s, 3H) ppm.

SYN

https://www.tandfonline.com/doi/abs/10.1080/13697130802054078?journalCode=icmt20

Estetrol (E4), or oestetrol, is a weak estrogen steroid hormone, which is found in detectable levels only during pregnancy in humans.[1][2] It is produced exclusively by the fetal liver.[1] Estetrol is closely related to estriol (E3), which is also a weak estrogen that is found in high quantities only during pregnancy.[1][2] Along with estradiol (E2), estrone (E1), and E3, estetrol (E4) is a major estrogen in the body, although only during pregnancy.[1]

In addition to its role as a natural hormone, estetrol is under clinical development for use as a medication, for instance in hormonal contraception (in combination with drospirenone) and as menopausal hormone therapy; for information on estetrol as a medication, see the estetrol (medication) article.

Biological function

Estetrol is an estrogen and has estrogenic effects in various tissues.[1] Estetrol interacts with nuclear Estrogen Receptor (ERα) in a manner identical to that of the other estrogens and distinct from that observed with Selective Estrogen Receptor Modulators (SERMs).[3][4] So far the physiological function of estetrol is unknown. The possible use of estetrol as a marker for fetal well-being has been studied quite extensively. However, due to the large intra- and inter-individual variation of maternal estetrol plasma levels during pregnancy this appeared not to be feasible.[5][6][7][8][9]

Biological activity

Estetrol is an agonist of the estrogen receptors (ERs), and hence is an estrogen.[10][11] It has moderate affinity for ERα and ERβ, with Ki values of 4.9 nM and 19 nM, respectively.[10][12] As such, estetrol has 4- to 5-fold preference for the ERα over the ERβ.[10][12] The estrogen has low affinity for the ERs relative to estradiol, and both estetrol and the related estrogen estriol require substantially higher concentrations than estradiol to produce similar effects to estradiol.[10] The affinity of estetrol for the ERs is about 0.3% (rat) to 6.25% (human) of that of estradiol, and its in vivo potency in animals is about 2 to 3% of that of estradiol.[10] Estetrol shows high selectivity for the ERs.[10][12]

Biochemistry

Biosynthesis

Estetrol is synthesized during pregnancy only in the fetal liver from estradiol (E2) and estriol (E3) by the two enzymes 15α- and 16α-hydroxylase.[13][14][15] Alternatively, estetrol is synthesized with 15α-hydroxylation of 16α-hydroxy-DHEA sulfate as an intermediate step.[16] It appears in maternal urine at around week 9 of pregnancy.[2] After birth the neonatal liver rapidly loses its capacity to synthesize estetrol because these two enzymes are no longer expressed.

Estetrol reaches the maternal circulation through the placenta and was already detected at nine weeks of pregnancy in maternal urine.[17][18] During the second trimester of pregnancy high levels were found in maternal plasma, with steadily rising concentrations of unconjugated estetrol to about 1 ng/mL (>3 nM) towards the end of pregnancy.[1]

Distribution

In terms of plasma protein binding, estetrol is moderately bound to albumin, and is not bound to sex hormone-binding globulin (SHBG).[19][20]

Metabolism

Estetrol undergoes no phase I metabolism by CYP P450 enzymes.[10] It is conjugated via glucuronidation and to a lesser extent sulfation and then excreted.[10][21]

Excretion

Estetrol is excreted mostly or completely in urine.[21][10]

Chemistry

See also: List of estrogens

vteStructures of major endogenous estrogensChemical structures of major endogenous estrogensEstrone (E1)Estradiol (E2)Estriol (E3)Estetrol (E4)The image above contains clickable linksNote the hydroxyl (–OH) groups: estrone (E1) has one, estradiol (E2) has two, estriol (E3) has three, and estetrol (E4) has four.

Estetrol, also known as 15α-hydroxyestriol or as estra-1,3,5(10)-triene-3,15α,16α,17β-tetrol, is a naturally occurring estrane steroid and derivative of estrin (estratriene).[10][11] It has four hydroxyl groups, which explains the abbreviation E4.[10][11]

Synthesis

Chemical syntheses of estetrol have been published.[22]

History

Estetrol was discovered in 1965 by Egon Diczfalusy and coworkers at the Karolinska Institute in Stockholm, Sweden, via isolation from the urine of pregnant women.[10][23]

References

  1. Jump up to:a b c d e f Holinka CF, Diczfalusy E, Coelingh Bennink HJ (May 2008). “Estetrol: a unique steroid in human pregnancy”. J. Steroid Biochem. Mol. Biol110 (1–2): 138–43. doi:10.1016/j.jsbmb.2008.03.027PMID 18462934.
  2. Jump up to:a b c Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management, 3rd ed., SSC Yen and RB Jaffe (eds.), pp. 936–981, Copyright Elsevier/Saunders 1991
  3. ^ Abot, Anne; Fontaine, Coralie; Buscato, Mélissa; Solinhac, Romain; Flouriot, Gilles; Fabre, Aurélie; Drougard, Anne; Rajan, Shyamala; Laine, Muriel; Milon, Alain; Muller, Isabelle (2014). “The uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor α modulation, uncoupling nuclear and membrane activation”EMBO Molecular Medicine6 (10): 1328–1346. doi:10.15252/emmm.201404112ISSN 1757-4676PMC 4287935PMID 25214462.
  4. ^ Foidart, JM; et al. (2019). “30th Annual Meeting of The North America Menopause Society September 25 – 28, 2019, Chicago, IL”Menopause26 (12): 1445–1481. doi:10.1097/GME.0000000000001456ISSN 1530-0374.
  5. ^ J. Heikkilä, T. Luukkainen, Urinary excretion of estriol and 15a-hydroxyestriol in complicated pregnancies, Am. J. Obstet. Gynecol. 110 (1971) 509-521.
  6. ^ D. Tulchinsky, F.D. Frigoletto, K.J. Ryan, J. Fishman, Plasma estetrol as an index of fetal well-being, J. Clin. Endocrinol. Metab. 40 (1975) 560-567
  7. ^ A.D. Notation, G.E. Tagatz, Unconjugated estriol and 15a-hydroxyestriol in complicated pregnancies, Am. J. Obstet. Gynecol. 128 (1977) 747-756.
  8. ^ N. Kundu, M. Grant, Radioimmunoassay of 15a-hydroxyestriol (estetrol) in pregnancy serum, Steroids 27 (1976) 785-796.
  9. ^ N. Kundu, M. Wachs, G.B. Iverson, L.P. Petersen, Comparison of serum unconjugated estriol and estetrol in normal and complicated pregnancies, Obstet. Gynecol. 58 (1981) 276-281.
  10. Jump up to:a b c d e f g h i j k l Coelingh Bennink HJ, Holinka CF, Diczfalusy E (2008). “Estetrol review: profile and potential clinical applications”. Climacteric. 11 Suppl 1: 47–58. doi:10.1080/13697130802073425PMID 18464023.
  11. Jump up to:a b c Visser M, Coelingh Bennink HJ (March 2009). “Clinical applications for estetrol” (PDF). J. Steroid Biochem. Mol. Biol114(1–2): 85–9. doi:10.1016/j.jsbmb.2008.12.013PMID 19167495.
  12. Jump up to:a b c Visser M, Foidart JM, Coelingh Bennink HJ (2008). “In vitro effects of estetrol on receptor binding, drug targets and human liver cell metabolism”. Climacteric. 11 Suppl 1: 64–8. doi:10.1080/13697130802050340PMID 18464025.
  13. ^ J. Schwers, G. Eriksson, N. Wiqvist, E. Diczfalusy, 15a-hydroxylation: A new pathway of estrogen metabolism in the human fetus and newborn, Biochim. Biophys. Acta. 100 (1965) 313-316
  14. ^ J. Schwers, M. Govaerts-Videtsky, N. Wiqvist, E. Diczfalusy, Metabolism of oestrone sulphate by the previable human foetus, Acta Endocrinol. 50 (1965) 597-610.
  15. ^ S. Mancuso, G. Benagiano, S. Dell’Acqua, M. Shapiro, N. Wiqvist, E. Diczfalusy, Studies on the metabolism of C-19 steroids in the human foeto-placental unit, Acta Endocrinol. 57 (1968) 208-227.
  16. ^ Jerome Frank Strauss; Robert L. Barbieri (2009). Yen and Jaffe’s Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management. Elsevier Health Sciences. pp. 262–. ISBN 1-4160-4907-X.
  17. ^ J. Heikkilä, H. Adlercreutz, A method for the determination of urinary 15α-hydroxyestriol and estriol, J. Steroid Biochem. 1 (1970) 243-253
  18. ^ J. Heikkilä, Excretion of 15α-hydroxyestriol and estriol in maternal urine during normal pregnancy, J. Steroid Biochem. 2 (1971) 83-93.
  19. ^ Visser M, Holinka CF, Coelingh Bennink HJ (2008). “First human exposure to exogenous single-dose oral estetrol in early postmenopausal women”. Climacteric. 11 Suppl 1: 31–40. doi:10.1080/13697130802056511PMID 18464021.
  20. ^ Hammond GL, Hogeveen KN, Visser M, Coelingh Bennink HJ (2008). “Estetrol does not bind sex hormone binding globulin or increase its production by human HepG2 cells”. Climacteric. 11 Suppl 1: 41–6. doi:10.1080/13697130701851814PMID 18464022.
  21. Jump up to:a b Mawet M, Maillard C, Klipping C, Zimmerman Y, Foidart JM, Coelingh Bennink HJ (2015). “Unique effects on hepatic function, lipid metabolism, bone and growth endocrine parameters of estetrol in combined oral contraceptives”Eur J Contracept Reprod Health Care20 (6): 463–75. doi:10.3109/13625187.2015.1068934PMC 4699469PMID 26212489.
  22. ^ Warmerdam EG, Visser M, Coelingh Bennink HJ, Groen M (2008). “A new route of synthesis of estetrol”. Climacteric. 11 Suppl 1: 59–63. doi:10.1080/13697130802054078PMID 18464024.
  23. ^ Hagen AA, Barr M, Diczfalusy E (June 1965). “Metabolism of 17-beta-oestradiol-4-14-C in early infancy”. Acta Endocrinol49: 207–20. doi:10.1530/acta.0.0490207PMID 14303250.
Names
Preferred IUPAC name(1R,2R,3R,3aS,3bR,9bS,11aS)-11a-Methyl-2,3,3a,3b,4,5,9b,10,11,11a-decahydro-1H-cyclopenta[a]phenanthrene-1,2,3,7-tetrol
Other namesOestetrol; E4; 15α-Hydroxyestriol; Estra-1,3,5(10)-triene-3,15α,16α,17β-tetrol
Identifiers
CAS Number15183-37-6 
3D model (JSmol)Interactive image
ChEBICHEBI:142773
ECHA InfoCard100.276.707 
KEGGD11513
PubChem CID27125
UNIIENB39R14VF 
CompTox Dashboard (EPA)DTXSID50164888 
showSMILES
Properties
Chemical formulaC18H24O4
Molar mass304.386 g/mol
Solubility in water1.38 mg/mL
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

//////////estetrol, Nextstellis, fda 2021, approvals 2021

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Nanatinostat


Nanatinostat Chemical Structure
ChemSpider 2D Image | CHR-3996 | C20H19FN6O2
Hdac inhibitor CHR-3996.png

Nanatinostat

Tractinostat

CHR-3996, CHR 3996, VRx 3996,

C20H19FN6O2, 394.41

CAS 1256448-47-1

2-[(1α,5α,6α)-6-[[(6-Fluoro-2-q

2-[(1R,5S,6R)-6-{[(6-fluoroquinolin-2-yl)methyl]amino}-3-azabicyclo[3.1.0]hexan-3-yl]-N-hydroxypyrimidine-5-carboxamide2-[(1R,5S,6s)-6-{[(6-Fluoro-2-quinolinyl)methyl]amino}-3-azabicyclo[3.1.0]hex-3-yl]-N-hydroxy-5-pyrimidinecarboxamide5-Pyrimidinecarboxamide, 2-[(1R,5S)-6-[[(6-fluoro-2-quinolinyl)methyl]amino]-3-azabicyclo[3.1.0]hex-3-yl]-N-hydroxy-Chroma Therapeutics Ltd. (Originator)

  • OriginatorChroma Therapeutics
  • DeveloperChroma Therapeutics; Viracta Therapeutics
  • ClassAmides; Antineoplastics; Pyrimidines; Quinolines; Small molecules
  • Mechanism of ActionHistone deacetylase inhibitors
  • Orphan Drug StatusYes – Post-transplant lymphoproliferative disorder; Plasmablastic lymphoma; T-cell lymphoma
  • Phase IILymphoma
  • Phase I/IIMultiple myeloma
  • Phase ISolid tumours
  • No development reportedGastric cancer; Nasopharyngeal cancer; Post-transplant lymphoproliferative disorder
  • 01 Jun 2021Phase-II clinical trials in Lymphoma (Combination therapy, Second-line therapy or greater) in North America, Europe, Asia (PO)
  • 18 May 2021Ninatinostat is still in phase I trials for Solid tumour in United Kingdom and Netherlands (Viracta Therapeutics pipeline, May 2021)
  • 18 May 2021Virata Therapeutics has patent protection for dose regimen in NAVAL-1 trial in USA

Nanatinostat is under investigation in clinical trial NCT00697879 (Safety Study of the Histone Deacetylase Inhibitor, CHR-3996, in Patients With Advanced Solid Tumours).

Nanatinostat is an orally bioavailable, second-generation hydroxamic acid-based inhibitor of histone deacetylase (HDAC), with potential antineoplastic activity. Nanatinostat targets and inhibits HDAC, resulting in an accumulation of highly acetylated histones, the induction of chromatin remodeling, and the selective transcription of tumor suppressor genes; these events result in the inhibition of tumor cell division and the induction of tumor cell apoptosis. This agent may upregulate HSP70 and downregulate anti-apoptotic Bcl-2 proteins more substantially than some first-generation HDAC inhibitors. HDACs, upregulated in many tumor cell types, are a family of metalloenzymes responsible for the deacetylation of chromatin histone proteins.

Patent

WO2006123121

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2006123121

Example 44: N-Hvdroxy 2-(6-fr(6-fluoroαuinolin-2-yl)methvnamino)-3-azabicvclorS.I.OIhex-S-vDpyrimidine-δ-carboxamide

LCMS purity >98%, m/z 395 [M+H]+1H NMR (300 MHz, c/6-DMSO) δ: 2.30 (2H, s), 2.75 (1 H, s), 3.60 (2H, dm, J = 11.7 Hz), 3.88 (2H, d, J = 11.7 Hz), 4.69 (2H, br s), 7.66 (1 H, d, J = 8.4 Hz), 7.75 (1 H, td, J = 8.7, 3.0 Hz), 7.88 (1 H, dd, J = 9.3, 2.7 Hz), 8.48 (1 H, d, J = 8.4 Hz), 8.67 (2H, s), 9.01 (1 H, br s), 9.61 (1 H, br s), 11.09 (1 H, br s).

PATENT

WO-2021113694

Crystalline hydrate form A of N-hydroxy 2-{6-[(6-fluoro-quinolin-2-ylmethyl)-amino]-3-aza-bicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxamide ( nanatinostat ) .

Compound 1 is also known as nanatinostat, VRx-3996, or CHR-3996. It has been previously described in patents and patent applications, e.g. US patent 7,932,246 and US patent application 15/959,482, each of which is incorporated by reference in their entirety.

Compound 1

PATENT

WO2021071809 , claiming dosages for HDAC treatment with reduced side effects.

/////////Nanatinostat, CHR-3996, CHR 3996, VRx 3996, CHROMA, ORPHAN DRUG, Tractinostat, PHASE 2

FC1=CC=C2N=C(CN[C@H]3[C@]4([H])CN(C5=NC=CC(C(NO)=O)=N5)C[C@]34[H])C=CC2=C1
wdt-13

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Drospirenone


Drospirenone.svg

Drospirenone

FDA APPROVED 4/15/2021, To prevent pregnancy Nextstellis

New Drug Application (NDA): 214154
Company: MAYNE PHARMALabel (PDF)
Letter (PDF)
ReviewLabel (PDF)DrospirenoneCAS Registry Number: 67392-87-4 
CAS Name: (2¢S,6R,7R,8R,9S,10R,13S,14S,15S,16S)-1,3¢,4¢,6,7,8,9,10,11,12,13,14,15,16,20,21-Hexadecahydro-10,13-dimethylspiro[17H-dicyclopropa[6,7:15,16]cyclopenta[a]phenanthrene-17,2¢(5¢H)-furan]-3,5¢(2H)-dione 
Additional Names: 6b,7b,15b,16b-dimethylene-3-oxo-4-androstene-[17(b-1¢)-spiro-5¢]perhydrofuran-2¢-one; 6b,7b,15b,16b-dimethylen-3-oxo-17a-pregn-4-ene-21,17-carbolactone; dihydrospirorenone 
Manufacturers’ Codes: ZK-30595 
Molecular Formula: C24H30O3Molecular Weight: 366.49Percent Composition: C 78.65%, H 8.25%, O 13.10% 
Literature References: Synthetic progestogen exhibiting antimineralocorticoid and antiandrogenic activity. Prepn: R. Wiechert et al.,DE2652761eidem,US4129564 (both 1978 to Schering AG); D. Bittler et al.,Angew. Chem.94, 718 (1982). HPLC determn in human plasma: W. Krause, U. Jakobs, J. Chromatogr.230, 37 (1982). Pharmacological profile: P. Muhn et al.,Contraception51, 99 (1995). Review of synthesis: H. Laurent et al.,J. Steroid Biochem.19, 771-776 (1983); of pharmacology and clinical experience: W. Oelkers, Mol. Cell. Endocrinol.217, 255-261 (2004). 
Properties: mp 201.3°. [a]D22 -182° (c = 0.5 in chloroform). uv (methanol): 265 nm (e 19000). 
Melting point: mp 201.3° 
Optical Rotation: [a]D22 -182° (c = 0.5 in chloroform) 
Derivative Type: Mixture with ethinyl estradiolTrademarks: Angeliq (Schering AG); Yasmin (Schering AG)Literature References: Clinical trial as oral contraceptive: K. S. Parsey, A. Pong, Contraception61, 105 (2000); in treatment of menopausal symptoms: R. Schürmann et al., Climacteric7, 189 (2004). 
Therap-Cat: Progestogen. In combination with estrogen as oral contaceptive and in treatment of menopausal symptoms.Keywords: Progestogen; Contraceptive (Oral).SYNhttps://www.sciencedirect.com/science/article/abs/pii/S0039128X15002135

Abstract

A general methodology for the synthesis of different steroidal 17-spirolactones is described. This method uses lithium acetylide of ethyl propiolate as the three carbon synthon and the method was successfully applied for the process development of drospirenone.

Graphical abstract

SYN

Steroid Hormones

Ruben Vardanyan, Victor Hruby, in Synthesis of Best-Seller Drugs, 2016

Drospirenone–Yaz

The synthesis of drospirenone (27.4.12) is believed to have been described for the first time in Wiechert et al [79], with a total yield of approximately 2 to 3% via the pathway presented in Scheme 27.4.

Each compound produced after each reaction step was purified by column chromatography.

Androsta-5,15-diene-3-ol-17-one was methylenated at the 15,16-position (27.4.13) and reacted with organometallic reagent (3,3-dimethoxypropyl)lithium prepared from 3-bromo-1,1-dimethoxypropane (27.4.14) and lithium in THF to produce the tertiary alcohol (27.4.15), which on short-term reflux with toluenesulfonic acid in acetone transformed to cyclic 21,17-hemiacetal (27.4.16). Oppenanuer oxidation with aluminium isopropoxide in excess of cyclohexanone in toluene was brought to mild oxidation of both secondary alcohol groups, and the simultaneous isomerization of the 5,6 double bond to the 4,5 position produced the compound (27.4.17). The last was oxidized with Jones reagent—chromic trioxide in diluted sulfuric acid—producing conjugated diene-one (27.4.18). Corey methylenation of the obtained product with dimethyloxosulfonium methylide in DMSO containing sodium hydride produced the final compound, the desired drospirenone (27.4.12).

The following patents and publications [80-83], which differ slightly from one another, disclose similar processes for preparing drospirenone and are presented in Scheme 27.5.

In Scheme 27.5, drospirenone (27.4.12) is prepared by converting the key starting compound (27.4.19) into the corresponding chloride (27.4.20) via reaction with triphenylphosphine and tetrachloromethane under mild conditions. Reductive dechlorination with Zn in acetic acid in THF tetrahydrofuran produced 5-hydroxy-15β,16β-methylene-3β-pivaloyloxy-5β-androst-6-en-17-one (27.4.21). The pivaloyl protecting group of the last was removed with the mixture of potassium hydroxide and sodium perchlorate in THF/methanol mixture to produce the diol (27.4.22). Simmons–Smith cyclopropanation reaction was applied to this compound. For that purpose, solution of (27.4.22) in dimethyl Cellosolve was stirred at 80°C with zinc-copper couple and methylene iodide, which produced the desired compound (27.4.23). The compound (27.4.23) underwent ethinylation with propargyl alcohol using potassium methylate in THF as a base to produce the 1,4-butindiol derivative (27.4.24). The triple bond of the 1,4-butindiol derivative (27.4.24) was hydrogenated in aTHF/methanol/pyridine mixture in the presence of palladium on carbon to produce the 1,4-butanediol derivative (27.4.25). The obtained compound underwent oxidation–lactonization at 50°C using a solution of CrO3 in water and pyridine to produce the desired drospirenone (27.4.12).

Several other synthetic routes for the production of drospirenone have been proposed [84-96], one of which [96] is presented in Scheme 27.6.

According to Scheme 27.6, a mixture of the key starting ketodiol (27.4.26), synthesis of which was described previously [84], with ethyl propiolate in THF was added to a solution of lithium hexamethyldisilylamide to produce, after quenching with acetic acid and saturated ammonium chloride solution, ethinyl alcohol (27.4.27). This product was hydrogenated on H2-Pd/C catalyst to produce ethyl 4-hydroxybutanoate (27.4.28). The 3-hydroxy group in the obtained product was oxidized to the keto group with (2,2,6,6-tetramethyl-piperidin-1-yl)oxyl, resulting in the compound (27.4.29). Treatment of the last with potassium hydroxide in a methanol–water mixture affects both hydrolysis of the ester group and dehydration of 5-hydroxy substituent. Acidification of the resulting intermediate results in drospirenone (27.4.12).

Drospirenone is a unique synthetic progestogen derived from 17α-spirolactone; it has a pharmacological profile very similar to that of endogenous progesterone. Drospirenone prevents ovulation and is used in contraceptive pills; it is also used as a postmenopausal hormone replacement. Drospirenone provides reliable and well-tolerated contraception and effective treatment of menopause. It has progestational, antialdosterone, and antiandrogenic properties, but is devoid of any estrogenic, androgenic, glucocorticoid, antiglucocorticoid, and mineralocorticoid activities. The affinity of drospirenone for the mineralocorticoid receptor makes it an antagonist of aldosterone, which is not only important in the renin–angiotensin–aldosterone system, but also means it acts directly on the cardiovascular system. It is progestin with antimineralocorticoid property that acts to suppress gonadotropins. It is thus able to prevent excessive sodium loss and regulate blood pressure. Drospirenone slightly decreases body weight and blood pressure and shares many pharmacodynamic properties with progesterone [97-110].

PATENT

https://patents.google.com/patent/US8334375B2/enDrospirenone is a synthetic steroid with progestin, anti-mineral corticoid and anti androgen activity. Drospirenone is currently being used as a synthetic progestin in oral contraceptive formulations. A regioselective synthesis for drospirenone has been described (see e.g., Angew. Chem. 94, 1982, 718) that uses the 17 keto derivative (1) as a key intermediate.

Figure US08334375-20121218-C00001

The synthesis of intermediate (1) and the transformation of intermediate (1) into drospirenone has been described in, for example, U.S. Published Patent Application Nos. 2009/0023914; 20080207575; 2008/0200668; 2008/0076915, 20070049747, and 20050192450; U.S. Pat. Nos. 6,933,395; 6,121,465, and 4,129,564, European Patent No. 0 075 189 and PCT Publication No. WO 2006/061309, all of which are incorporated herein by reference. Many of these routes introduce the required C3 side chain in the 17 position of intermediate (1). These conversions are usually carried out with carbanions, such as propargylalcohol, trimethylsulfoxonium iodide, or the use of the anion generated from a suitably protected derivative of 1-bromopropionaldehyde. After oxidation of the 3-hydroxy substituent to a 3-keto group, and the oxidative formation of the 17-spirolactone, the 3-keto-5-hydroxy-17-spirolactone is transformed via acid catalysis into drospireneone. If the oxidation is performed under acidic conditions at elevated temperatures, the oxidation and elimination can be run without isolation of the intermediate products.Most of these procedures rely on the acid-catalyzed elimination of the 5-hydroxy group in the last step of the synthesis. It has been documented that 15,16-methylene-17-spirolactones are prone to undergo rearrangement to generate the inverted 17-spirolactone under mild acidic conditions (see, for example, Tetrahedron Letters, Vol. 27, No 45, 5463-5466) in considerable amounts. This isomer has very similar physical chemical properties, and typically requires chromatographic separation or repeated fractional recrystallizations to purify the product. This isomerization can make these approaches less desirable from an economical point of view.FIG. 1Experimental Example

Figure US08334375-20121218-C00022

A solution of compound (1) (5 g; 15.2 mmol) and tert-butyldimethyl (2-propynyloxy)silane (2.83 g, 16.7 mmol) in 75 ml of dry THF was added dropwise through an addition funnel to a precooled slurry of potassium tert-butoxide (8.49 g, 75.7 mmol) at −10 C. A thick white precipitate is formed during the addition and the resulting mixture was stirred for an hour at 0 C. TLC analysis (70% EtOAc/Hexanes) showed completion of the reaction and showed a less polar product. The reaction was quenched by the addition of ice water (100 ml) and neutralized by adding acetic acid (4.3 ml). The THF layer was separated and the aqueous layer was extracted with EtOAc (2×50 ml). The combined organic layers were washed with water (2×100 ml), brine (100 ml) and dried over anhydrous sodium sulfate. The solvent was removed under vacuum to afford compound (2a) (7.5 g, 99.2%) as a solid which was used in the next step without any purification.NMR (CDCl3) δ 0.139 (s, 6H, S1—CH3), 0.385 (m, 1H), 0.628 (m, 1H), 0.857 (s, 18-Me), 0.896 (s, 19-Me), 0.918 (s, 3H, Si—CH3), 0.927 (s, 6H, Si—CH3), 4.05 (s, 1H), 4.428 (s, 2H, —O—CH2) FTIR (ATR): 3311, 3017, 2929, 2858, 2270, 1058 cm−1

Figure US08334375-20121218-C00023

Compound (2a) (5 g, 9.98 mmol) was dissolved in 100 ml of ethyl acetate in a Parr hydrogenation bottle and was mixed with 10% palladium on charcoal (1 g, 0.09 mmol). This mixture was hydrogenated on a Parr apparatus at a pressure of 20 psi for 90 minutes. The catalyst was filtered and washed with ethyl acetate. The solvent was removed in vacuo to afford compound (3a) as a colorless foam (5.01 g, 99%).NMR (CDCl3) δ 0.0758 (s, 6H, Si—CH3), 0.283 (m, 1H), 0.628 (m, 1H), 0.856 (s, 18-Me), 0.893 (s, 19-Me), 0.918 (s, 9H, Si—CH3), 3.69 (m, 2H), 4.05 (s, 1H). FTIR (ATR): 3374, 3017, 2929, 2858, 1259, 1091, 1049, 835 cm−1

Figure US08334375-20121218-C00024

Chromium trioxide (4.95 g, 49.5 mmol) was added to a solution of pyridine (7.83 g, 99.05 mmol) in anhydrous dichloromethane (100 ml). The resulting mixture was stirred for 15 minutes during which time the color changed to burgundy. A solution of compound (1a) (5 g, 9.90 mmol) in 50 ml of dichloromethane was added and the mixture was stirred at room temperature for 6 h. The excess oxidizing agent was quenched by adding isopropanol. The reaction mixture was diluted with MTBE (50 ml) and was passed through a short pad of Celite. The solid was washed again with 2:1 MTBE-CH2Cl(50 ml x2). The solvent was removed in vacuo to give a residue which was dissolved in 100 ml of EtOAc, was washed with water, and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to afford compound (4a) as a pale yellow foam (4.5 g, 90.3%).NMR (CDCl3) δ 0.08 (s, 6H, Si—CH3), 0.31 (m, 1H), 0.914 (s, 9H, Si—CH3), 0.931 (s, 6H, 18-Me, 19-Me) 3.70 (m, 2H). FTIR (ATR): 3399, 3022, 2950, 2929, 2862, 1708, 1649, 1259, 1041 cm−1

Figure US08334375-20121218-C00025

A solution of compound (4a) (5 g, 9.94 mmol) in 50 ml of MeOH was refluxed with NaOH (397 mg, 9.94 mmol) for 3 h. When the reaction was over, as shown by TLC, the reaction mixture was cooled to room temperature and added to ice cold water (150 ml). The mixture was extracted with ethyl acetate (3×50 mL). The combined EtOAc layers were washed with water (100 ml) brine (50 ml) and dried over sodium sulfate. The solvent was removed in vacuo to afford compound (5) as a colorless amorphous solid (4.5 g, 92%).NMR (CDCl3) δ 0.05 (s, 6H, Si—CH3), 0.296 (m, 1H), 0.886 (s, 9H, Si—CH3), 0.908 (s, 3H, 18-Me), 1.07 (s, 3H, 19-Me), 3.68 (m, 2-H), 5.95 (s, 1H). FTIR (ATR): 3450, 3009, 2950, 2858, 1653, 1603, 1095 cm−1

Figure US08334375-20121218-C00026

A solution of compound (5a) (5 g, 9.94 mmol) in 30 ml of acetone was cooled to −15 C as a 2.7M solution of Jones reagent (3.68 ml, 9.94 mmol) was added drop wise. The reaction mixture was stirred at 0 C for 2 h, during this time TLC showed completion of the reaction. The reaction was quenched by adding isopropanol and diluted with water. The reaction mixture was extracted with EtOAc. The combined EtOAc layers were washed with water, sat. NaHCOand brine. The EtOAc layers were dried over sodium sulfate and solvent was removed by vacuum to afford crude drospirenone as a pale yellow foam (3 g, 82%) Recrystallization from acetone-hexane gave 1.5 g of pure drospirenone as white solid.NMR (CDCl3) δ 0.0548 (m, 1H), 0.88 (m, 1H), 1.008 (s, 3H, 18-Me), 1.11 (s, 3H, 18-Me), 6.03 (s, 1H). FTIR (ATR): 3025, 2971, 2942, 1763, 1654, 1590, 1186 cm−1FIG. 2Experimental Example

Figure US08334375-20121218-C00027

Lithium hexamethyldisilylamide (LiHMDS) 1.0 M/THF (75.7 mL, 75.7 mmol) was introduced into a 500 mL, 3-neck flask equipped with an addition funnel and a pierced septa for the introduction of a thermocouple probe. The mixture was diluted with THF (25 mL). The solution was stirred (Teflon paddle) and chilled to an internal temperature of −72° C. A THF (75 mL) solution of ketodiol (5 g, 15.13 mmol) containing ethyl propiolate (3.07 mL, 30.26 mmol) was added dropwise over 1 hour while not allowing the temperature to rise above −65° C. Upon completion of the addition the mixture was stirred for 3 hrs while allowing the temperature to warm slowly to −60° C. Finally, the mixture was warned to −40° C. over 1 hour.The mixture was quenched through the addition of acetic acid (4.25 mL)/water (5.0 mL) followed by the addition of saturated ammonium chloride solution (100 mL). The mixture was stirred for 3 min and then transferred to a separatory funnel. The layers were separated and the upper, THF layer was diluted with ethyl acetate (75 mL). The organic phase was washed with water (3×100 mL) and brine (1×100 mL). All the aqueous washes were extracted with ethyl acetate (2×30 mL). The combined organic extract was dried over sodium sulfate, filtered, and evaporated in vacuo (45° C.) to afford a thick oil. Dichloromethane (ca. 35 mL) was added and evaporated in vacuo. The flask was cooled slightly and dichloromethane (33 ml) was added to give a solid mass. The solid was broken up and stirred until a homogeneous slurry was obtained. Hexanes (35 mL) was added slowly to the stirred mixture and the mixture was stored at 2-4 C overnight. The solid was filtered, washed with 30% dichloromethane/hexanes, and dried in vacuo at ambient temperature for 4 hours to give (2b) 5.86 g (90.4%) of a white powder.

Figure US08334375-20121218-C00028

Compound (2b) (5.0 g, 11.67 mmol) was dissolved in THF (50 mL) and 5% Pd/C (622 mg, 0.29 mmol Pd) was added and the mixture was shaken at 15 psi Hfor 2 hours. The mixture was diluted with ethyl acetate (25 mL) and filtered through a pad of Celite. The filter pad was washed with ethyl acetate (3×25 mL) and the filtrate was evaporated to dryness to afford 5.0 g (99.1%) of triol (7b) as a stable foam.

Figure US08334375-20121218-C00029

Compound (7a) (5.0 g, 11.56 mmol) was dissolved in dichloromethane (50 mL) and the solution was stirred vigorously and chilled to −15° C. (NaCl/ice) and TEMPO (45.16 mg, 0.29 mmol, 2.5 mol %) was added. The mixture was treated dropwise over about 15-20 min. with a mixture of sodium hypochlorite (12.5%) (11.17 mL, 23.12 mmol) in water (8.0 mL) containing potassium bicarbonate (833 mg, 8.32 mmol). The mixture was allowed to warm to 0 C for 1.25 hrs. Analysis of the reaction by TLC (60% EtOAc/hex) shows the appearance of a slightly less polar product (ΔRf=0.8 cm). The mixture was chilled to −5 C and was quenched through the dropwise addition (ca 10-15 min) of a water (15.0 mL) solution of sodium phosphate (1.27 g, 7.75 mmol) and sodium metabisulfite (1.10 g, 5.78 mmol). The layers were separated and the dichloromethane solution was washed with water (2×) and brine. All aqueous washes were extracted with additional dichloromethane (2×15 mL). The combined dichloromethane extract was dried over sodium sulfate, filtered, and evaporated to give 4.88 g (98.08%) of ketone (8b) as a stable foam.

Figure US08334375-20121218-C00030

Compound (8b) was added to a methanol (10 mL) solution containing 8.0 M KOH solution (6.3 mL, 50.36 mmol) preheated to 60 C. The solution was heated at reflux for 2.5 hours. The mixture was chilled in an ice bath and treated with acetic acid (36 mL) and water (5.0 mL). The solution was stirred at 50-60 C for 15 hours. The volatiles were evaporated in vacuo and the acetic acid solution was poured into cold water (150 mL) to give a white precipitate. The aqueous mixture was extracted with ethyl acetate (2×100 mL). The ethyl acetate extracts were washed with water (2×), saturated sodium bicarbonate solution, and brine. The combined ethyl acetate extract was dried over sodium sulfate. Evaporation of the solvent gave a yellow foam. Trituration of the foam with acetone/hexane followed by evaporation gave 4.27 g (92.62%) of a light yellow solid. Recrystallization of the solid from acetone/hexanes gave 3.07 g of drospirenone with an HPLC purity of 99.66%. Evaporation of the mother liquor and recrystallization of the residue affords an additional 0.54 g of slightly impure drospirenone.FIG. 3Experimental Example

Figure US08334375-20121218-C00031

Lithium hexamethyldisilylamide (LiHMDS) 1.0 M/THF (75.7 mL, 75.7 mmol) was introduced into a 500 mL, 3-neck flask equipped with an addition funnel and a pierced septa for the introduction of a thermocouple probe. The mixture was diluted with THF (25 mL). The solution was stirred (Teflon paddle) and chilled to an internal temperature of −72° C. A THF (75 mL) solution of ketodiol (5 g, 15.13 mmol) containing ethyl propiolate (3.07 mL, 30.26 mmol) was added dropwise over 1 hour while not allowing the temperature to rise above −65° C. Upon completion of the addition the mixture was stirred for 3 hrs while allowing the temperature to warm slowly to −60° C. Finally, the mixture was warmed to −40° C. over 1 hour.The mixture was quenched through the addition of acetic acid (4.25 mL)/water (5.0 mL) followed by the addition of saturated ammonium chloride solution (100 mL). The mixture was stirred for 3 min and then transferred to a separatory funnel. The layers were separated and the upper, THF layer was diluted with ethyl acetate (75 mL). The organic phase was washed with water (3×100 mL) and brine (1×100 mL). All the aqueous washes were extracted with ethyl acetate (2×30 mL). The combined organic extract was dried over sodium sulfate, filtered, and evaporated in vacuo (45° C.) to afford a thick oil. Dichloromethane (ca. 35 mL) was added and evaporated in vacuo. The flask was cooled slightly and dichloromethane (33 ml) was added to give a solid mass. The solid was broken up and stirred until a homogeneous slurry was obtained. Hexanes (35 mL) was added slowly to the stirred mixture and the mixture was stored at 2-4 C overnight. The solid was filtered, washed with 30% dichloromethane/hexanes, and dried in vacuo at ambient temperature for 4 hours to give (2c) 5.86 g (90.4%) of a white powder.

Figure US08334375-20121218-C00032

Propiolate adduct (2c) (5.86 g, 13.67 mmol) was suspended in dichloromethane (60 mL). The mixture was stirred vigorously and chilled to −15° C. (NaCl/ice) and TEMPO (54 mg, 0.35 mmol, 2.5 mol %) was added. The mixture was treated dropwise over about 15-20 min. with a mixture of sodium hypochlorite (12.5%) (13.2 mL, 27.34 mmol) in water (8.0 mL) containing potassium bicarbonate (985 mg, 9.84 mmol). During the addition of the hypochlorite solution, a 5-8 C temperature rise was observed and the mixture became yellow. The mixture was allowed to warm to at 0 C for 2 hrs. Analysis of the reaction by TLC (60% EtOAc/hex) shows the appearance of a slightly less polar product (ΔRf=0.8 cm). The mixture was chilled to −5 C and was quenched through the dropwise addition (ca 10-15 min) of a water (150 mL) solution of sodium phosphate (1.50 g, 9.16 mmol) and sodium metabisulfite (1.30 g, 6.84 mmol). Once again, a temperature rise of 5-8 C was observed and the yellow color was quenched. The layers were separated and the dichloromethane solution was washed with water (2×) and brine. All aqueous washes were extracted with additional dichloromethane (2×15 mL). The combined dichloromethane extract was dried over sodium sulfate and the bulk of the solvent was evaporated in vacuo. Upon the observation of solids in the mixture during the evaporation, the evaporation was discontinued and the residue in the flask diluted with MTBE (35 mL). While stirring, the mixture was slowly diluted with hexanes (35 mL). The mixture was then chilled in an ice bath for 30 min. The solid was filtered, washed with 25% MTBE/hexane, and dried to give intermediate (9c) (4.98 g, 85.31%) as a white solid.NMR (CDCl3) δ 0.462 (q, 1H), 0.699 (m, 1H), 0.924 (s, 18-Me), 0.952 (s, 19-Me), 1.338 (t, J=7 Hz, OCH2CH 3), 2.517 (d, 1H), 3.021 (d, 1H), 4.269 (t, OCH 2CH3) ppm. FTIR (ATR): 3493, 3252, 2948, 2226, 1697, 1241 cm−1.

Figure US08334375-20121218-C00033

Alkynyl ketone (9c) (5.37 g, 12.59 mmol) was dissolved in THF (27 mL) in a 250 mL shaker bottle. 5% Pd/C (670 mg, 2.5 mol %) was added to the solution and the mixture was shaken under a hydrogen pressure of 15 psi. Over approximately 30 min, there was observed a rapid up take of hydrogen. The pressure was continually adjusted to 15 psi until the uptake of hydrogen ceased and was shaken for a total of 1.5 hrs. The mixture was diluted with a small amount of methanol and filtered through Celite. The filter pad was washed with methanol (ca. 3×25 mL).NMR (CDCl3) δ 0.353 (q, 1H), 0.704 (m, 2H), 0.930 (s, 18-Me), 0.933 (s, 19-Me), 1.279 (t, J=7 Hz, OCH2CH 3), 2.480 (d, 1H), 2.672 (m, 2H), 3.981 (d, 1H), 4.162 (t, OCH 2CH3) ppm. FTIR (ATR): 3465, 2946, 1712, cm−1.

Figure US08334375-20121218-C00034

The filtrate containing compound (8c) described above, was added in one portion to a methanol (10 mL) solution containing 8.0 M KOH solution (6.3 mL, 50.36 mmol) preheated to 60 C. The solution was heated at reflux for 2.5 hours. The mixture was chilled in an ice bath and treated with acetic acid (36 mL) and water (5.0 mL). The solution was stirred at 50-60 C for 15 hours. The volatiles were evaporated in vacuo and the acetic acid solution was poured into cold water (150 mL) to give a white precipitate. The aqueous mixture was extracted with ethyl acetate (2×100 mL). The ethyl acetate extracts were washed with water (2×), saturated sodium bicarbonate solution, and brine. The combined ethyl acetate extract was dried over sodium sulfate. Evaporation of the solvent gave a yellow foam. Trituration of the foam with acetone/hexane followed by evaporation gave 4.27 g (92.62%) of a light yellow solid. Recrystallization of the solid from acetone/hexanes gave 3.07 g of drospirenone with an HPLC purity of 99.66%. Evaporation of the mother liquor and recrystallization of the residue affords an additional 0.54 g of slightly impure drospirenone.FIG. 4Experimental Example

Figure US08334375-20121218-C00035

Lithium hexamethyldisilylamide (LiHMDS) 1.0 M/THF (75.7 mL, 75.7 mmol) was introduced into a 500 mL, 3-neck flask equipped with an addition funnel and a pierced septa for the introduction of a theiniocouple probe. The mixture was diluted with THF (25 mL). The solution was stirred (Teflon paddle) and chilled to an internal temperature of −72° C. A THF (75 mL) solution of ketodiol (5 g, 15.13 mmol) containing ethyl propiolate (3.07 mL, 30.26 mmol) was added dropwise over 1 hour while not allowing the temperature to rise above −65° C. Upon completion of the addition the mixture was stirred for 3 hrs while allowing the temperature to warm slowly to −60° C. Finally, the mixture was warmed to −40° C. over 1 hour.The mixture was quenched through the addition of acetic acid (4.25 mL)/water (5.0 mL) followed by the addition of saturated ammonium chloride solution (100 mL). The mixture was stirred for 3 min and then transferred to a separatory funnel. The layers were separated and the upper, THF layer was diluted with ethyl acetate (75 mL). The organic phase was washed with water (3×100 mL) and brine (1×100 mL). All the aqueous washes were extracted with ethyl acetate (2×30 mL). The combined organic extract was dried over sodium sulfate, filtered, and evaporated in vacuo (45° C.) to afford a thick oil. Dichloromethane (ca. 35 mL) was added and evaporated in vacuo. The flask was cooled slightly and dichloromethane (33 ml) was added to give a solid mass. The solid was broken up and stirred until a homogeneous slurry was obtained. Hexanes (35 mL) was added slowly to the stirred mixture and the mixture was stored at 2-4 C overnight. The solid was filtered, washed with 30% dichloromethane/hexanes, and dried in vacuo at ambient temperature for 4 hours to give (2d) 5.86 g (90.4%) of a white powder.

Figure US08334375-20121218-C00036

Propiolate adduct (2d) (5.86 g, 13.67 mmol) was suspended in dichloromethane (60 mL). The mixture was stirred vigorously and chilled to −15° C. (NaCl/ice) and TEMPO (54 mg, 0.35 mmol, 2.5 mol %) was added. The mixture was treated dropwise over about 15-20 min. with a mixture of sodium hypochlorite (12.5%) (13.2 mL, 27.34 mmol) in water (8.0 mL) containing potassium bicarbonate (985 mg, 9.84 mmol). During the addition of the hypochlorite solution, a 5-8 C temperature rise was observed and the mixture became yellow. The mixture was allowed to warm to at 0 C for 2 hrs. Analysis of the reaction by TLC (60% EtOAc/hex) shows the appearance of a slightly less polar product (ΔRf=0.8 cm). The mixture was chilled to −5 C and was quenched through the dropwise addition (ca 10-15 min) of a water (15.0 mL) solution of sodium phosphate (1.50 g, 9.16 mmol) and sodium metabisulfite (1.30 g, 6.84 mmol). Once again, a temperature rise of 5-8 C was observed and the yellow color was quenched. The layers were separated and the dichloromethane solution was washed with water (2×) and brine. All aqueous washes were extracted with additional dichloromethane (2×15 mL). The combined dichloromethane extract was dried over sodium sulfate and the bulk of the solvent was evaporated in vacuo. Upon the observation of solids in the mixture during the evaporation, the evaporation was discontinued and the residue in the flask diluted with MTBE (35 mL). While stirring, the mixture was slowly diluted with hexanes (35 mL). The mixture was then chilled in an ice bath for 30 min. The solid was filtered, washed with 25% MTBE/hexane, and dried to give intermediate (9d) (4.98 g, 85.31%) as a white solid.NMR (CDCl3) δ 0.462 (q, 1H), 0.699 (m, 1H), 0.924 (s, 18-Me), 0.952 (s, 19-Me), 1.338 (t, J=7 Hz, OCH2CH 3), 2.517 (d, 1H), 3.021 (d, 1H), 4.269 (t, OCH 2CH3) ppm. FTIR (ATR): 3493, 3252, 2948, 2226, 1697, 1241 cm−1.

Figure US08334375-20121218-C00037

Compound (9d) (5.0 g) was dissolved in methanol (50 mL) and treated with 1.0 N sulfuric acid (10 mL). The mixture was heated to reflux for 3 hours, cooled, and neutralized through the addition of saturated sodium bicarbonate solution. Most of the methanol was evaporated in vacuo at ambient temperature and diluted with water. The aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with water and brine, dried over sodium sulfate, filtered, and evaporated to give 4.95 g of unsaturated ketone (10d) as a stable foam.

Figure US08334375-20121218-C00038

Compound (10d) (5.0 g, 12.24 mmol) was dissolved in degassed benzene (50 mL) and treated with chlorotris(triphenylphosphine)rhodium (I) (283.1 mg, 0.31 mmol and the resulting mixture was stirred in a hydrogen atmosphere for 10 hours. The solution was evaporated, reconstituted in 50% ethyl acetate/hexanes, and passed through a short column of neutral alumina. Evaporation of the solvent gave 4.95 g of (11d) as a stable foam.

Figure US08334375-20121218-C00039

Compound (11d) (4.95 g, 12.01 mmol) was dissolved in 10% aqueous methanol (50 mL) and solid potassium carbonate (4.98 g, 36.04 mmol) was added. The mixture was stirred at room temperature for 30 min and the bicarbonate was neutralized through the addition of acetic acid (2.06 mL, 36.04 mmol). The methanol was evaporated in vacuo at ambient temperature and diluted with water. The aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with water and brine, dried over sodium sulfate, filtered, and evaporated to give 4.10 g (93%) of a semi solid. The material was dissolved in dichloromethane and evaporated in vacuo to give a stable foam. The foam was dissolved in ethyl acetate (5 mL) and allowed to stand overnight. The resulting solid was filtered, washed with cold ethyl acetate, and dried in vacuo to afford 2.86 g (66%) of pure drospirenone.FIG. 5Experimental Example 1

Figure US08334375-20121218-C00040

A dichloromethane (50 mL) solution of ketodiol (1) (5.0 g, 15.13 mmol) was treated with ethyl vinyl ether (7.24 mL, 75.65 mmol), followed by the addition of pyridinium tosylate (380 mg, 1.15 mmol). The solution was stirred at room temperature for 30 min. The dichloromethane solution was washed with water (2×), brine, and dried over sodium sulfate. Following filtration, evaporation of the solvent gave 6.14 g of the 3-protected compound (1e) as a stable foam.

Figure US08334375-20121218-C00041

Compound (1e) (6.14 g, 15.13 mmol) was dissolved in DMSO/THF (15 mL/15 mL), treated with trimethylsulfonium iodide (4.63 g, 22.70 mmol) and the mixture was chilled to −15 C. The mixture was treated portion wise with potassium t-butoxide (3.23 g, 28.82 mmol). The mixture was stirred at −15 C for 45 min and then poured into ice/water (200 mL). The aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with water (2×) and brine, dried over sodium sulfate, and filtered. Evaporation of the solvent gave 6.21 g (98.42%) of oxirane (12e) as a stable foam.

Figure US08334375-20121218-C00042

A THF (30 mL) solution of di-isopropyl amine (12.02 mL, 85.03 mmol) was chilled to −40 C and treated with butyl lithium (2.5 M/hexanes, 34.01 mL, 85.03 mmol) and the mixture was stirred for 15 min. A THF (5 mL) solution of acetonitrile (4.7 mL, 90.79 mmol) was added dropwise to the in situ generated lithium di-isopropylamide (LDA) solution to give a slurry of the acetonitrile anion. After stirring for 15 min at −40° C., compound (12e) (6.21 g, 14.91 mmol) as a THF (25 mL) solution was added dropwise over 10 min. The mixture was stirred for 30 min and then quenched through the addition of saturated ammonium chloride solution (210 mL). The mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with water (3×) and brine, dried over sodium sulfate, and filtered. Evaporation of the solvent gave 7.07 g of the addition product (13e) as a tacky foam.

Figure US08334375-20121218-C00043

Compound 13e (5.0 g, 10.93 mmol) was dissolved in acetone (25 mL) and chilled to 0 C. The stirred solution was treated dropwise with 2.7M chromic acid (Jones Reagent) (7.0 mL, 18.91 mmol). After 1.5 hrs, the excess Cr (VI) was quenched through the addition of 2-propanol until the green color of Cr (IV) was evident. Water (300 mL) was added and the mixture was stirred until all the chromium salts were dissolved. The aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with water (2×) and brine, dried over sodium sulfate, and filtered. Evaporation of the solvent gave 3.83 g (96%) of ketone (14e) as a stable foam.

Figure US08334375-20121218-C00044

Compound (14e) (3.83 g, 10.48 mmol) was dissolved in methanol (38 mL) and treated with 8.0 M KOH solution (7.0 mL, 56 mmol) and the mixture was heated at reflux for 5 hours. The mixture was cooled to 0 C and treated with acetic acid (15 mL) and water (6 mL) and the mixture was stirred at 50 C for 6 hours. The solvents were evaporated in vacuo and the residue was diluted with water (200 mL). The aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with water (2×) and brine, dried over sodium sulfate, and filtered. Evaporation of the solvent gave 3.76 g (94%) of crude drospirenone as a stable foam. The crude drospirenone was dissolved in 60% ethyl acetate/hexanes and passed through a short column of neutral alumina (10× w/w) and the column was eluted with the same solvent. Following evaporation of the solvent, 2.58 g (65%) of crystalline drospirenone was obtained. Recrystallization from acetone/hexanes afforded pure drospirenone.FIG. 5Experimental Example 2

Figure US08334375-20121218-C00045

Intermediate (1) (5 g, 15.13 mmol) was dissolved in DMSO/THF (50 mL/50 mL), treated with trimethylsulfonium iodide (4.63 g, 22.70 mmol), and the mixture was chilled to −15 C. The mixture was treated portion wise with potassium t-butoxide (5.03 g, 43.88 mmol). The mixture was stirred at −15 C for 45 min and then poured into ice/water (200 mL). The aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with water (2×) and brine, dried over sodium sulfate, and filtered. Evaporation of the solvent gave 5.11 g (98%) of oxirane (12f) as a stable foam.

Figure US08334375-20121218-C00046

A THF (30 mL) solution of di-isopropyl amine (12.02 mL, 85.03 mmol) was chilled to −40 C and treated with butyl lithium (2.5 M/hexanes, 34.01 mL, 85.03 mmol) and the mixture was stirred for 15 min. A THF (5 mL) solution of acetonitrile (4.7 mL, 90.79 mmol) was added dropwise to the above lithium di-isopropylamide (LDA) solution to give a slurry of the acetonitrile anion. After stirring for 15 min at −40 C, compound (12f) (5.11 g, 14.83 mmol) as a THF (75 mL) solution was added dropwise over 10 min. The mixture was stirred for 30 min and then quenched through the addition of saturated ammonium chloride solution (300 mL). The mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with water (3×) and brine, dried over sodium sulfate, and filtered. Evaporation of the solvent gave 5.75 g of addition product (13f) as a tacky foam.

Figure US08334375-20121218-C00047

Compound 13f (5.75 g, 14.95 mmol) was dissolved in acetone (25 mL) and chilled to 0 C. The stirred solution was treated dropwise with 2.7M chromic acid (Jones Reagent) until the orange color of Cr (VI) persisted. After 1.5 hrs, the excess Cr (VI) was quenched through the addition of 2-propanol until the green color of Cr (IV) was evident. Water (300 mL) was added and the mixture was stirred until all the chromium salts were dissolved. The aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with water (2×) and brine, dried over sodium sulfate, and filtered. Evaporation of the solvent gave 5.5 g (96%) of ketone (14f) as a stable foam.

Figure US08334375-20121218-C00048

Compound (14f) (5.5 g, 14.38 mmol) was dissolved in methanol (50 mL) and treated with 8.0 M KOH solution (9.35 mL, 74.77 mmol) and the mixture was heated at reflux for 5 hours. The mixture was cooled to 0 C and treated with acetic acid (25 mL) and water (10 mL) and the mixture was stirred at 50 C for 6 hours. The solvents were evaporated in vacuo and the residue was diluted with water (300 mL). The aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with water (2×) and brine, dried over sodium sulfate, and filtered. Evaporation of the solvent gave 4.95 g (94%) of crude drospirenone as a stable foam. The crude drospirenone was dissolved in 60% ethyl acetate/hexanes and passed through a short column of neutral alumina (10× w/w) and the column was eluted with the same solvent. Following evaporation of the solvent, 3.43 g (65%) of crystalline drospirenone was obtained. Recrystallization from acetone/hexanes afforded pure drospirenone.

Drospirenone is a progestin medication which is used in birth control pills to prevent pregnancy and in menopausal hormone therapy, among other uses.[1][7] It is available both alone under the brand name Slynd and in combination with an estrogen under the brand name Yasmin among others.[7][2] The medication is taken by mouth.[2][1]

Common side effects include acneheadachebreast tendernessweight increase, and menstrual changes.[2] Rare side effects may include high potassium levels and blood clots, among others.[2][8] Drospirenone is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone.[1] It has additional antimineralocorticoid and antiandrogenic activity and no other important hormonal activity.[1] Because of its antimineralocorticoid activity and lack of undesirable off-target activity, drospirenone is said to more closely resemble bioidentical progesterone than other progestins.[9][10]

Drospirenone was patented in 1976 and introduced for medical use in 2000.[11][12] It is available widely throughout the world.[7] The medication is sometimes referred to as a “fourth-generation” progestin.[13][14] It is available as a generic medication.[15] In 2018, a formulation of drospirenone with ethinylestradiol was the 167th most commonly prescribed medication in the United States, with more than 3 million prescriptions.[16][17]

Medical uses

Drospirenone (DRSP) is used by itself as a progestogen-only birth control pill, in combination with the estrogens ethinylestradiol (EE) or estetrol (E4), with or without supplemental folic acid (vitamin B9), as a combined birth control pill, and in combination with the estrogen estradiol (E2) for use in menopausal hormone therapy.[2] A birth control pill with low-dose ethinylestradiol is also indicated for the treatment of moderate acnepremenstrual syndrome (PMS), premenstrual dysphoric disorder (PMDD), and dysmenorrhea (painful menstruation).[18][19] For use in menopausal hormone therapy, E2/DRSP is specifically approved to treat moderate to severe vasomotor symptoms (hot flashes), vaginal atrophy, and postmenopausal osteoporosis.[20][21][22] The drospirenone component in this formulation is included specifically to prevent estrogen-induced endometrial hyperplasia.[23] Drospirenone has also been used in combination with an estrogen as a component of hormone therapy for transgender women.[24][25]

Studies have found that EE/DRSP is superior to placebo in reducing premenstrual emotional and physical symptoms while also improving quality of life.[26][27] E2/DRSP has been found to increase bone mineral density and to reduce the occurrence of bone fractures in postmenopausal women.[28][23][29][30] In addition, E2/DRSP has a favorable influence on cholesterol and triglyceride levels and decreases blood pressure in women with high blood pressure.[29][30] Due to its antimineralocorticoid activity, drospirenone opposes estrogen-induced salt and water retention and maintains or slightly reduces body weight.[31]

Available forms

Drospirenone is available in the following formulations, brand names, and indications:[32][33]

Contraindications

Contraindications of drospirenone include renal impairment or chronic kidney diseaseadrenal insufficiency, presence or history of cervical cancer or other progestogen-sensitive cancersbenign or malignant liver tumors or hepatic impairment, undiagnosed abnormal uterine bleeding, and hyperkalemia (high potassium levels).[2][45][46] Renal impairment, hepatic impairment, and adrenal insufficiency are contraindicated because they increase exposure to drospirenone and/or increase the risk of hyperkalemia with drospirenone.[2]

Side effects

Adverse effects of drospirenone alone occurring in more than 1% of women may include unscheduled menstrual bleeding (breakthrough or intracyclic) (40.3–64.4%), acne (3.8%), metrorrhagia (2.8%), headache (2.7%), breast pain (2.2%), weight gain (1.9%), dysmenorrhea (1.9%), nausea (1.8%), vaginal hemorrhage (1.7%), decreased libido (1.3%), breast tenderness (1.2%), and irregular menstruation (1.2%).[2]

High potassium levels

Drospirenone is an antimineralocorticoid with potassium-sparing properties, though in most cases no increase of potassium levels is to be expected.[45] In women with mild or moderate chronic kidney disease, or in combination with chronic daily use of other potassium-sparing medications (ACE inhibitorsangiotensin II receptor antagonistspotassium-sparing diureticsheparin, antimineralocorticoids, or nonsteroidal anti-inflammatory drugs), a potassium level should be checked after two weeks of use to test for hyperkalemia.[45][47] Persistent hyperkalemia that required discontinuation occurred in 2 out of around 1,000 women (0.2%) with 4 mg/day drospirenone alone in clinical trials.[2]

Blood clots

Birth control pills containing ethinylestradiol and a progestin are associated with an increased risk of venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE).[48] The incidence is about 4-fold higher on average than in women not taking a birth control pill.[48] The absolute risk of VTE with ethinylestradiol-containing birth control pills is small, in the area of 3 to 10 out of 10,000 women per year, relative to 1 to 5 out of 10,000 women per year not taking a birth control pill.[49][50] The risk of VTE during pregnancy is 5 to 20 in 10,000 women per year and during the postpartum period is 40 to 65 per 10,000 women per year.[50] The higher risk of VTE with combined birth control pills is thought to be due to the ethinylestradiol component, as ethinylestradiol has estrogenic effects on liver synthesis of coagulation factors which result in a procoagulatory state.[8] In contrast to ethinylestradiol-containing birth control pills, neither progestogen-only birth control nor the combination of transdermal estradiol and an oral progestin in menopausal hormone therapy is associated with an increased risk of VTE.[8][51]

Different progestins in ethinylestradiol-containing birth control pills have been associated with different risks of VTE.[8] Birth control pills containing progestins such as desogestrelgestodene, drospirenone, and cyproterone acetate have been found to have 2- to 3-fold the risk of VTE of birth control pills containing levonorgestrel in retrospective cohort and nested case–control observational studies.[8][49] However, this area of research is controversial, and confounding factors may have been present in these studies.[8][49][52] Other observational studies, specifically prospective cohort and case control studies, have found no differences in risk between different progestins, including between birth control pills containing drospirenone and birth control pills containing levonorgestrel.[8][49][52][53] These kinds of observational studies have certain advantages over the aforementioned types of studies, like better ability to control for confounding factors.[53] Systematic reviews and meta-analyses of all of the data in the mid-to-late 2010s found that birth control pills containing cyproterone acetate, desogestrel, drospirenone, or gestodene overall were associated with a risk of VTE of about 1.3- to 2.0-fold compared to that of levonorgestrel-containing birth control pills.[54][55][49]

Androgenic progestins have been found to antagonize to some degree the effects of ethinylestradiol on coagulation.[56][57][58][59] As a result, more androgenic progestins, like levonorgestrel and norethisterone, may oppose the procoagulatory effects of ethinylestradiol and result in a lower increase in risk of VTE.[8][60] Conversely, this would be the case less or not at all with progestins that are less androgenic, like desogestrel and gestodene, as well as progestins that are antiandrogenic, like drospirenone and cyproterone acetate.[8][60]

In the early 2010s, the FDA updated the label for birth control pills containing drospirenone and other progestins to include warnings for stopping use prior to and after surgery, and to warn that such birth control pills may have a higher risk of blood clots.[46]

Breast cancer

Drospirenone has been found to stimulate the proliferation and migration of breast cancer cells in preclinical research, similarly to certain other progestins.[61][62] However, some evidence suggests that drospirenone may do this more weakly than certain other progestins, like medroxyprogesterone acetate.[61][62] The combination of estradiol and drospirenone has been found to increase breast density, an established risk factor for breast cancer, in postmenopausal women.[63][64][65]

Data on risk of breast cancer in women with newer progestins like drospirenone are lacking at present.[66] Progestogen-only birth control is not generally associated with a higher risk of breast cancer.[66] Conversely, combined birth control and menopausal hormone therapy with an estrogen and a progestogen are associated with higher risks of breast cancer.[67][66][68]

Overdose

These have been no reports of serious adverse effects with overdose of drospirenone.[2] Symptoms that may occur in the event of an overdose may include nauseavomiting, and vaginal bleeding.[2] There is no antidote for overdose of drospirenone and treatment of overdose should be based on symptoms.[2] Since drospirenone has antimineralocorticoid activity, levels of potassium and sodium should be measured and signs of metabolic acidosis should be monitored.[2]

Interactions

Inhibitors and inducers of the cytochrome P450 enzyme CYP3A4 may influence the levels and efficacy of drospirenone.[2] Treatment for 10 days with 200 mg twice daily ketoconazole, a strong CYP3A4 inhibitor among other actions, has been found to result in a moderate 2.0- to 2.7-fold increase in exposure to drospirenone.[2] Drospirenone does not appear to influence the metabolism of omeprazole (metabolized via CYP2C19), simvastatin (metabolized via CYP3A4), or midazolam (metabolized via CYP3A4), and likely does not influence the metabolism of other medications that are metabolized via these pathways.[2] Drospirenone may interact with potassium-sparing medications such as ACE inhibitorsangiotensin II receptor antagonistspotassium-sparing diureticspotassium supplementsheparinantimineralocorticoids, and nonsteroidal anti-inflammatory drugs to further increase potassium levels.[2] This may increase the risk of hyperkalemia (high potassium levels).[2]

Pharmacology

Pharmacodynamics

Drospirenone binds with high affinity to the progesterone receptor (PR) and mineralocorticoid receptor (MR), with lower affinity to the androgen receptor (AR), and with very low affinity to the glucocorticoid receptor (GR).[1][69][70][4] It is an agonist of the PR and an antagonist of the MR and AR, and hence is a progestogenantimineralocorticoid, and antiandrogen.[1][69][4][62] Drospirenone has no estrogenic activity and no appreciable glucocorticoid or antiglucocorticoid activity.[1][69][4][62]

Progestogenic activity

Drospirenone is an agonist of the PR, the biological target of progestogens like progesterone.[1][69] It has about 35% of the affinity of promegestone for the PR and about 19 to 70% of the affinity of progesterone for the PR.[1][3][62] Drospirenone has antigonadotropic and functional antiestrogenic effects as a result of PR activation.[1][69] The ovulation-inhibiting dosage of drospirenone is 2 to 3 mg/day.[72][73][1][74] Inhibition of ovulation occurred in about 90% of women at a dose of 0.5 to 2 mg/day and in 100% of women at a dose of 3 mg/day.[75] The total endometrial transformation dose of drospirenone is about 50 mg per cycle, whereas its daily dose is 2 mg for partial transformation and 4 to 6 mg for full transformation.[1][76][75] The medication acts as a contraceptive by activating the PR, which suppresses the secretion of luteinizing hormone, inhibits ovulation, and alters the cervical membrane and endometrium.[77][2]

Due to its antigonadotropic effects, drospirenone inhibits the secretion of the gonadotropinsluteinizing hormone (LH) and follicle-stimulating hormone (FSH), and suppresses gonadal sex hormone production, including of estradiolprogesterone, and testosterone.[1][78][3] Drospirenone alone at 4 mg/day has been found to suppress estradiol levels in premenopausal women to about 40 to 80 pg/mL depending on the time of the cycle.[78] No studies of the antigonadotropic effects of drospirenone or its influence on hormone levels appear to have been conducted in men.[79][80][81] In male cynomolgus monkeys however, 4 mg/kg/day oral drospirenone strongly suppressed testosterone levels.[69]

Antimineralocorticoid activity

Drospirenone is an antagonist of the MR, the biological target of mineralocorticoids like aldosterone, and hence is an antimineralocorticoid.[69] It has about 100 to 500% of the affinity of aldosterone for the MR and about 50 to 230% of the affinity of progesterone for the MR.[1][3][71][62] Drospirenone is about 5.5 to 11 times more potent as an antimineralocorticoid than spironolactone in animals.[69][75][82] Accordingly, 3 to 4 mg drospirenone is said to be equivalent to about 20 to 25 mg spironolactone in terms of antimineralocorticoid activity.[83][2] It has been said that the pharmacological profile of drospirenone more closely resembles that of progesterone than other progestins due to its antimineralocorticoid activity.[69] Drospirenone is the only clinically used progestogen with prominent antimineralocorticoid activity besides progesterone.[1] For comparison to progesterone, a 200 mg dose of oral progesterone is considered to be approximately equivalent in antimineralocorticoid effect to a 25 to 50 mg dose of spironolactone.[84] Both drospirenone and progesterone are actually weak partial agonists of the MR in the absence of mineralocorticoids.[4][3][62]

Due to its antimineralocorticoid activity, drospirenone increases natriuresis, decreases water retention and blood pressure, and produces compensatory increases in plasma renin activity as well as circulating levels and urinary excretion of aldosterone.[3][85][1] This has been shown to occur at doses of 2 to 4 mg/day.[3] Similar effects occur during the luteal phase of the menstrual cycle due to increased progesterone levels and the resulting antagonism of the MR.[3] Estrogens, particularly ethinylestradiol, activate liver production of angiotensinogen and increase levels of angiotensinogen and angiotensin II, thereby activating the renin–angiotensin–aldosterone system.[3][1] As a result, they can produce undesirable side effects including increased sodium excretion, water retention, weight gain, and increased blood pressure.[3] Progesterone and drospirenone counteract these undesirable effects via their antimineralocorticoid activity.[3] Accumulating research indicates that antimineralocorticoids like drospirenone and spironolactone may also have positive effects on adipose tissue and metabolic health.[86][87]

Antiandrogenic activity

Drospirenone is an antagonist of the AR, the biological target of androgens like testosterone and dihydrotestosterone (DHT).[1][3] It has about 1 to 65% of the affinity of the synthetic anabolic steroid metribolone for the AR.[1][3][4][62] The medication is more potent as an antiandrogen than spironolactone, but is less potent than cyproterone acetate, with about 30% of its antiandrogenic activity in animals.[1][88][69][75] Progesterone displays antiandrogenic activity in some assays similarly to drospirenone,[3] although this issue is controversial and many researchers regard progesterone as having no significant antiandrogenic activity.[89][1][4]

Drospirenone shows antiandrogenic effects on the serum lipid profile, including higher HDL cholesterol and triglyceride levels and lower LDL cholesterol levels, at a dose of 3 mg/day in women.[3] The medication does not inhibit the effects of ethinylestradiol on sex hormone-binding globulin (SHBG) and serum lipids, in contrast to androgenic progestins like levonorgestrel but similarly to other antiandrogenic progestins like cyproterone acetate.[3][1][74] SHBG levels are significantly higher with ethinylestradiol and cyproterone acetate than with ethinylestradiol and drospirenone, owing to the more potent antiandrogenic activity of cyproterone acetate relative to drospirenone.[90] Androgenic progestins like levonorgestrel have been found to inhibit the procoagulatory effects of estrogens like ethinylestradiol on hepatic synthesis of coagulation factors, whereas this may occur less or not at all with weakly androgenic progestins like desogestrel and antiandrogenic progestins like drospirenone.[8][60][56][57][58][59]

Other activity

Drospirenone stimulates the proliferation of MCF-7 breast cancer cells in vitro, an action that is independent of the classical PRs and is instead mediated via the progesterone receptor membrane component-1 (PGRMC1).[91] Certain other progestins act similarly in this assay, whereas progesterone acts neutrally.[91] It is unclear if these findings may explain the different risks of breast cancer observed with progesterone and progestins in clinical studies.[66]

Pharmacokinetics

Absorption

The oral bioavailability of drospirenone is between 66 and 85%.[1][3][4] Peak levels occur 1 to 6 hours after an oral dose.[1][3][2][82] Levels are about 27 ng/mL after a single 4 mg dose.[2] There is 1.5- to 2-fold accumulation in drospirenone levels with continuous administration, with steady-state levels of drospirenone achieved after 7 to 10 days of administration.[1][2][3] Peak levels of drospirenone at steady state with 4 mg/day drospirenone are about 41 ng/mL.[2] With the combination of 30 μg/day ethinylestradiol and 3 mg/day drospirenone, peak levels of drospirenone after a single dose are 35 ng/mL, and levels at steady state are 60 to 87 ng/mL at peak and 20 to 25 ng/mL at trough.[3][1] The pharmacokinetics of oral drospirenone are linear with a single dose across a dose range of 1 to 10 mg.[2][3] Intake of drospirenone with food does not influence the absorption of drospirenone.[2]

Distribution

The distribution half-life of drospirenone is about 1.6 to 2 hours.[3][1] The apparent volume of distribution of drospirenone is approximately 4 L/kg.[2] The plasma protein binding of drospirenone is 95 to 97%.[2][1] It is bound to albumin and 3 to 5% circulates freely or unbound.[2][1] Drospirenone has no affinity for sex hormone-binding globulin (SHBG) or corticosteroid-binding globulin (CBG), and hence is not bound by these plasma proteins in the circulation.[1]

Metabolism

The metabolism of drospirenone is extensive.[3] It is metabolized into the acid form of drospirenone by opening of its lactone ring.[1][2] The medication is also metabolized by reduction of its double bond between the C4 and C5 positions and subsequent sulfation.[1][2] The two major metabolites of drospirenone are drospirenone acid and 4,5-dihydrodrospirenone 3-sulfate, and are both formed independently of the cytochrome P450 system.[2][3] Neither of these metabolites are known to be pharmacologically active.[2] Drospirenone also undergoes oxidative metabolism by CYP3A4.[2][3][5][6]

Elimination

Drospirenone is excreted in urine and feces, with slightly more excreted in feces than in urine.[2] Only trace amounts of unchanged drospirenone can be found in urine and feces.[2] At least 20 different metabolites can be identified in urine and feces.[3] Drospirenone and its metabolites are excreted in urine about 38% as glucuronide conjugates, 47% as sulfate conjugates, and less than 10% in unconjugated form.[3] In feces, excretion is about 17% glucuronide conjugates, 20% sulfate conjugates, and 33% unconjugated.[3]

The elimination half-life of drospirenone is between 25 and 33 hours.[2][3][1] The half-life of drospirenone is unchanged with repeated administration.[2] Elimination of drospirenone is virtually complete 10 days after the last dose.[3][2]

Chemistry

See also: SpirolactoneList of progestogens § Spirolactone derivatives, and List of steroidal antiandrogens § Spirolactone derivatives

vteChemical structures of spirolactonesSpirolactone structuresProgesteroneSpirolactoneCanrenoneSpironolactoneDrospirenoneSpirorenoneThe image above contains clickable linksChemical structures of progesterone and spirolactones (steroid-17α-spirolactones).

Drospirenone, also known as 1,2-dihydrospirorenone or as 17β-hydroxy-6β,7β:15β,16β-dimethylene-3-oxo-17α-pregn-4-ene-21-carboxylic acid, γ-lactone, is a synthetic steroidal 17α-spirolactone, or more simply a spirolactone.[7][92] It is an analogue of other spirolactones like spironolactonecanrenone, and spirorenone.[7][92] Drospirenone differs structurally from spironolactone only in that the C7α acetylthio substitution of spironolactone has been removed and two methylene groups have been substituted in at the C6β–7β and C15β–16β positions.[93]

Spirolactones like drospirenone and spironolactone are derivatives of progesterone, which likewise has progestogenic and antimineralocorticoid activity.[94][95][96] The loss of the C7α acetylthio group of spironolactone, a compound with negligible progestogenic activity,[97][98] appears to be involved in the restoration of progestogenic activity in drospirenone, as SC-5233, the analogue of spironolactone without a C7α substitution, has potent progestogenic activity similarly to drospirenone.[99]

History

Drospirenone was patented in 1976 and introduced for medical use in 2000.[11][12] Schering AG of Germany has been granted several patents on the production of drospirenone, including WIPO and US patents, granted in 1998 and 2000, respectively.[100][101] It was introduced for medical use in combination with ethinylestradiol as a combined birth control pill in 2000.[11] Drospirenone is sometimes described as a “fourth-generation” progestin based on its time of introduction.[13][14] The medication was approved for use in menopausal hormone therapy in combination with estradiol in 2005.[20] Drospirenone was introduced for use as a progestogen-only birth control pill in 2019.[2] A combined birth control pill containing estetrol and drospirenone was approved in 2021.[102]

Society and culture

Generic names

Drospirenone is the generic name of the drug and its INNUSANBAN, and JAN, while drospirénone is its DCF.[7] Its name is a shortened form of the name 1,2-dihydrospirorenone or dihydrospirenone.[7][92] Drospirenone is also known by its developmental code names SH-470 and ZK-30595 (alone), BAY 86-5300BAY 98-7071, and SH-T-00186D (in combination with ethinylestradiol), BAY 86-4891 (in combination with estradiol), and FSN-013 (in combination with estetrol).[7][92][103][104][105][106][102]

Brand names

Drospirenone is marketed in combination with an estrogen under a variety of brand names throughout the world.[7] Among others, it is marketed in combination with ethinylestradiol under the brand names Yasmin and Yaz, in combination with estetrol under the brand name Nextstellis, and in combination with estradiol under the brand name Angeliq.[7][102]

Availability

See also: List of progestogens available in the United States

Drospirenone is marketed widely throughout the world.[7]

Generation

Drospirenone has been categorized as a “fourth-generation” progestin.[62]

Litigation

Many lawsuits have been filed against Bayer, the manufacturer of drospirenone, due to the higher risk of venous thromboembolism (VTE) that has been observed with combined birth control pills containing drospirenone and certain other progestins relative to the risk with levonorgestrel-containing combined birth control pills.[52]

In July 2012, Bayer notified its stockholders that there were more than 12,000 such lawsuits against the company involving Yaz, Yasmin, and other birth control pills with drospirenone.[107] They also noted that the company by then had settled 1,977 cases for US$402.6 million, for an average of US$212,000 per case, while setting aside US$610.5 million to settle the others.[107]

As of July 17, 2015, there have been at least 4,000 lawsuits and claims still pending regarding VTE related to drospirenone.[108] This is in addition to around 10,000 claims that Bayer has already settled without admitting liability.[108] These claims of VTE have amounted to US$1.97 billion.[108] Bayer also reached a settlement for arterial thromboembolic events, including stroke and heart attacks, for US$56.9 million.[108]

Research

See also: Estetrol/drospirenone and Ethinylestradiol/drospirenone/prasterone

A combination of ethinylestradiol, drospirenone, and prasterone is under development by Pantarhei Bioscience as a combined birth control pill for prevention of pregnancy in women.[109] It includes prasterone (dehydroepiandrosterone; DHEA), an oral androgen prohormone, to replace testosterone and avoid testosterone deficiency caused by suppression of testosterone by ethinylestradiol and drospirenone.[109] As of August 2018, the formulation is in phase II/III clinical trials.[109]

Drospirenone has been suggested for potential use as a progestin in male hormonal contraception.[79]

Drospirenone has been studied in forms for parenteral administration.[110][111][112][113]

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  89. ^ Yeh YT, Chang CW, Wei RJ, Wang SN (2013). “Progesterone and related compounds in hepatocellular carcinoma: basic and clinical aspects”Biomed Res Int2013: 290575. doi:10.1155/2013/290575PMC 3581253PMID 23484104.
  90. ^ Schindler, Adolf E. (2015). “Hormonal Contraceptives: Progestogen and Thrombotic Risk”. Frontiers in Gynecological Endocrinology. ISGE Series. pp. 69–75. doi:10.1007/978-3-319-09662-9_8ISBN 978-3-319-09661-2ISSN 2197-8735.
  91. Jump up to:a b Neubauer H, Ma Q, Zhou J, Yu Q, Ruan X, Seeger H, Fehm T, Mueck AO (October 2013). “Possible role of PGRMC1 in breast cancer development”. Climacteric16 (5): 509–13. doi:10.3109/13697137.2013.800038PMID 23758160S2CID 29808177.
  92. Jump up to:a b c d Martin Negwer; Hans-Georg Scharnow (4 October 2001). Organic-chemical drugs and their synonyms: (an international survey). Wiley-VCH. p. 2539. ISBN 978-3-527-30247-5.
  93. ^ Howard J.A. Carp (9 April 2015). Progestogens in Obstetrics and Gynecology. Springer. pp. 115–. ISBN 978-3-319-14385-9.
  94. ^ Ménard J (2004). “The 45-year story of the development of an anti-aldosterone more specific than spironolactone”. Mol. Cell. Endocrinol217 (1–2): 45–52. doi:10.1016/j.mce.2003.10.008PMID 15134800S2CID 19701784[Spironolactone] was synthesized after the demonstration of the natriuretic effect of progesterone (Landau et al., 1955).
  95. ^ J. Larry Jameson; Leslie J. De Groot (18 May 2010). Endocrinology – E-Book: Adult and Pediatric. Elsevier Health Sciences. pp. 2401–. ISBN 978-1-4557-1126-0[Spironolactone] is a potent antimineralocorticoid which was developed as a progestational analog […]
  96. ^ Aldosterone. Elsevier Science. 23 January 2019. p. 46. ISBN 978-0-12-817783-9In addition to spironolactone, which is a derivative of progesterone […]
  97. ^ Hu X, Li S, McMahon EG, Lala DS, Rudolph AE (2005). “Molecular mechanisms of mineralocorticoid receptor antagonism by eplerenone”. Mini Rev Med Chem5 (8): 709–18. doi:10.2174/1389557054553811PMID 16101407.
  98. ^ Nakajima ST, Brumsted JR, Riddick DH, Gibson M (1989). “Absence of progestational activity of oral spironolactone”. Fertil. Steril52 (1): 155–8. doi:10.1016/s0015-0282(16)60807-5PMID 2744183.
  99. ^ Hertz R, Tullner WW (1958). “Progestational activity of certain steroid-17-spirolactones”. Proc. Soc. Exp. Biol. Med99 (2): 451–2. doi:10.3181/00379727-99-24380PMID 13601900S2CID 20150966.
  100. ^ WO patent 9806738, Mohr, Jörg-Thorsten & Klaus Nickisch, “PROCESS FOR PRODUCING DROSPIRENONE (6ss,7ss;15ss,16ss-DIMETHYLENE-3-OXO-17 alpha -PREGN-4-EN-21,17-CARBOLACTONE, DRSP), AS WELL AS 7 alpha -(3-HYDROXY-1-PROPYL)-6ss,7ss;15ss,16ss-DIMETHYLENE-5ss-ANDROSTANE-3ss,5,17ss-TRIOL (ZK 92836) AND 6ss,7ss;15ss,16ss-DIMETHYLENE-5ss HYDROXY-5-OXO-17 alpha -ANDROSTANE-21, 17-CARBOLACTONE”, issued 1998-02-19, assigned to Shering AG
  101. ^ US patent 6121465, Mohr, Joerg-Thorston & Klaus Nickisch, “Process for production drospirenone and intermediate products of the process”, issued 2000-09-19, assigned to Scheiring AG and Bayer Schering Pharma
  102. Jump up to:a b c “Drospirenone/Estetrol – Mithra Pharmaceuticals – AdisInsight”.
  103. ^ “Ethinylestradiol/drospirenone – AdisInsight”.
  104. ^ “Ethinylestradiol/drospirenone/folic acid – AdisInsight”.
  105. ^ “Drospirenone/ethinylestradiol low-dose – Bayer HealthCare Pharmaceuticals – AdisInsight”.
  106. ^ “Estradiol/drospirenone – Bayer HealthCare Pharmaceuticals – AdisInsight”.
  107. Jump up to:a b Feeley, Jef; Kresge, Naomi (July 31, 2012). “Bayer’s Yasmin lawsuit settlements rise to $402.6 million”Bloomberg News. New York. Retrieved November 11, 2012.
  108. Jump up to:a b c d AG, Bayer. “Quarterly Reports of Bayer”http://www.bayer.com.
  109. Jump up to:a b c “Drospirenone/estradiol/prasterone – ANI Pharmaceuticals/Pantarhei Bioscience – AdisInsight”adisinsight.springer.com.
  110. ^ Nippe S, General S (September 2011). “Parenteral oil-based drospirenone microcrystal suspensions-evaluation of physicochemical stability and influence of stabilising agents”. Int J Pharm416 (1): 181–8. doi:10.1016/j.ijpharm.2011.06.036PMID 21729745.
  111. ^ Nippe S, General S (November 2012). “Combination of injectable ethinyl estradiol and drospirenone drug-delivery systems and characterization of their in vitro release”. Eur J Pharm Sci47 (4): 790–800. doi:10.1016/j.ejps.2012.08.009PMID 22940138.
  112. ^ Nippe S, Preuße C, General S (February 2013). “Evaluation of the in vitro release and pharmacokinetics of parenteral injectable formulations for steroids”. Eur J Pharm Biopharm83 (2): 253–65. doi:10.1016/j.ejpb.2012.09.006PMID 23116659.
  113. ^ Nippe S, General S (April 2015). “Investigation of injectable drospirenone organogels with regard to their rheology and comparison to non-stabilized oil-based drospirenone suspensions”. Drug Dev Ind Pharm41 (4): 681–91. doi:10.3109/03639045.2014.895375PMID 24621345S2CID 42932558.

Further reading

External links

Clinical data
PronunciationDroe-SPY-re-nown
Trade namesAlone: Slynd
With estradiol: Angeliq
With ethinylestradiol: Yasmin, Yasminelle, Yaz, others
With estetrol: Nextstellis
Other namesDihydrospirenone; Dihydrospirorenone; 1,2-Dihydrospirorenone; MSp; SH-470; ZK-30595; LF-111; 17β-Hydroxy-6β,7β:15β,16β-dimethylene-3-oxo-17α-pregn-4-ene-21-carboxylic acid, γ-lactone
AHFS/Drugs.comProfessional Drug Facts
License dataUS DailyMedDrospirenone
Routes of
administration
By mouth[1]
Drug classProgestogenProgestinAntimineralocorticoidSteroidal antiandrogen
ATC codeG03AC10 (WHO)
G03AA12 (WHOG03FA17 (WHO) (combinations with estrogens)
Legal status
Legal statusAU: S4 (Prescription only)US: ℞-only [2]In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability66–85%[1][3][4]
Protein binding95–97% (to albumin)[2][1][3]
MetabolismLiver (mostly CYP450-independent (reductionsulfation, and cleavage of lactone ring), some CYP3A4 contribution)[3][5][6]
Metabolites• Drospirenone acid[2]
• 4,5-Dihydrodrospirenone 3-sulfate[2]
Elimination half-life25–33 hours[2][3][1]
ExcretionUrinefeces[2]
Identifiers
showIUPAC name
CAS Number67392-87-4 
PubChem CID68873
DrugBankDB01395 
ChemSpider62105 
UNIIN295J34A25
KEGGD03917 
ChEBICHEBI:50838 
ChEMBLChEMBL1509 
CompTox Dashboard (EPA)DTXSID7046465 
ECHA InfoCard100.060.599 
Chemical and physical data
FormulaC24H30O3
Molar mass366.501 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI
  (verify)

//////////drospirenone, Nextstellis, ZK 30595, FDA 2021, APPROVALS 2021

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Samidorphan


Samidorphan structure.svg
852626-89-2.png

Samidorphan

サミドルファン;

FormulaC21H26N2O4
CAS852626-89-2
Mol weight370.4421

FDA  APPROVED 5/28/2021 Lybalvi

  • ALKS 33
  • ALKS-33
  • RDC-0313
  • RDC-0313-00

Product Ingredients

Thumb
ChemSpider 2D Image | Samidorphan L-malate | C25H32N2O9

UNII0AJQ5N56E0

CAS Number1204592-75-5

WeightAverage: 504.536
Monoisotopic: 504.210780618

Chemical FormulaC25H32N2O9

INGREDIENTUNIICASINCHI KEY
Samidorphan L-malate0AJQ5N56E01204592-75-5RARHXUAUPNYAJF-QSYGGRRVSA-N

IUPAC Name(1R,9R,10S)-17-(cyclopropylmethyl)-3,10-dihydroxy-13-oxo-17-azatetracyclo[7.5.3.0^{1,10}.0^{2,7}]heptadeca-2,4,6-triene-4-carboxamide; (2S)-2-hydroxybutanedioic acid

MOA:mu-Opioid antagonist; delta-Opioid partial agonist; kappa-Opioid partial agonistsIndication:Alcohol dependence

New Drug Application (NDA): 213378
Company: ALKERMES INChttps://www.accessdata.fda.gov/drugsatfda_docs/label/2021/213378s000lbl.pdfhttps://www.accessdata.fda.gov/drugsatfda_docs/appletter/2021/213378Orig1s000,%20Orig2s000ltr.pdf

To treat schizophrenia in adults and certain aspects of bipolar I disorder in adults

LYBALVI is a combination of olanzapine, an atypical antipsychotic, and samidorphan (as samidorphan L-malate), an opioid antagonist.

Olanzapine is 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine. The molecular formula of olanzapine is: C17H20N4S and the molecular weight is 312.44 g/mol. It is a yellow crystalline powder and has pKa values of 7.80 and 5.44. The chemical structure is:

Olanzapine Structural Formula - Illustration

Samidorphan L-malate is morphinan-3-carboxamide, 17-(cyclopropylmethyl)-4, 14-dihydroxy-6-oxo-, (2S)-2-hydroxybutanedioate. The molecular formula of samidorphan L-malate is C21H26N2O4 • C4H6O5 and the molecular weight is 504.54 g/mol. It is a white to off-white crystalline powder and has pKa values of 8.3 (amine) and 10.1 (phenol). The chemical structure is:

Samidorphan Structural Formula - Illustration

LYBALVI is intended for oral administration and is available as film-coated, bilayer tablets in the following strengths: 5 mg/10 mg, 10 mg/10 mg, 15 mg/10 mg, and 20 mg/10 mg of olanzapine and samidorphan (equivalent to 13.6 mg of samidorphan L-malate).

Inactive ingredients include colloidal silicon dioxide, crospovidone, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. The film coating ingredients include hypromellose, titanium dioxide, triacetin, and color additives [iron oxide yellow (5 mg/10 mg); iron oxide yellow and iron oxide red (10 mg/10 mg); FD&C Blue No. 2/ indigo carmine aluminum lake (15 mg/10 mg); iron oxide red (20 mg/10 mg)].

  • to treat schizophrenia
  • alone for short-term (acute) or maintenance treatment of manic or mixed episodes that happen with bipolar I disorder
  • in combination with valproate or lithium to treat manic or mixed episodes that happen with bipolar I disorder

Olanzapine is an effective atypical antipsychotic that, like other antipsychotics, is associated with weight gain, metabolic dysfunction, and increased risk of type II diabetes.5,6 Samidorphan is a novel opioid antagonist structurally related to naltrexone, with a higher affinity for opioid receptors, more potent μ-opioid receptor antagonism, higher oral bioavailability, and a longer half-life, making it an attractive candidate for oral dosing.1,5,11 Although antipsychotic-induced weight gain is incompletely understood, it is thought that the opioid system plays a key role in feeding and metabolism, such that opioid antagonism may be expected to ameliorate these negative effects. Samidorphan has been shown in animal models and clinical trials to ameliorate olanzapine-induced weight gain and metabolic dysfunction.5,6

Samidorphan was first approved as a variety of fixed-dose combination tablets with olanzapine by the FDA on May 28, 2021, and is currently marketed under the trademark LYBALVI™ by Alkermes Inc.11

Samidorphan (INNUSAN) (developmental code names ALKS-33RDC-0313), also known as 3-carboxamido-4-hydroxynaltrexone,[2] is an opioid antagonist that preferentially acts as an antagonist of the μ-opioid receptor (MOR). It is under development by Alkermes for the treatment of major depressive disorder and possibly other psychiatric conditions.[3]

Development

Samidorphan has been investigated for the treatment of alcoholism and cocaine addiction by its developer, Alkermes,[4][5] showing similar efficacy to naltrexone but possibly with reduced side effects.

However, it has attracted much more attention as part of the combination product ALKS-5461 (buprenorphine/samidorphan), where samidorphan is combined with the mixed MOR weak partial agonist and κ-opioid receptor (KOR) antagonist buprenorphine, as an antidepressant. Buprenorphine has shown antidepressant effects in some human studies, thought to be because of its antagonist effects at the KOR, but has not been further developed for this application because of its MOR agonist effects and consequent abuse potential. By combining buprenorphine with samidorphan to block the MOR agonist effects, the combination acts more like a selective KOR antagonist, and produces only antidepressant effects, without typical MOR effects such as euphoria or substance dependence being evident.[6][7]

Samidorphan is also being studied in combination with olanzapine, as ALKS-3831 (olanzapine/samidorphan), for use in schizophrenia.[8] A Phase 3 study found that the addition of samidorphan to olanzapine significantly reduced weight gain compared to olanzapine alone.[9] The combination is now under review for approval by the US Food and Drug Administration.[10]

Pharmacology

Pharmacodynamics

The known activity profile of samidorphan at the opioid receptors is as follows:[11][12]

As such, samidorphan is primarily an antagonist, or extremely weak partial agonist of the MOR.[11][12] In accordance with its in vitro profile, samidorphan has been observed to produce some side effects that are potentially consistent with activation of the KOR such as somnolencesedationdizziness, and hallucinations in some patients in clinical trials at the doses tested.[13]

SYNPATENT

WO2006052710A1.

https://patents.google.com/patent/WO2006052710A1/enExample 1 -Synthesis of 3-Carboxyamido-4-hvdroxy-naltrexone derivative 3

Figure imgf000020_0001

(A) Synthesis of 3-Carboxyamido-naltrexone 2[029] The triflate 11 of naltrexone was prepared according to the method of Wentland et al. (Bioorg. Med. Chem. Lett. 9, 183-187 (2000)), and the carboxamide 2 was prepared by the method described by Wentland et al. [(Bioorg. Med. Chem. Lett. ϋ, 623-626 (2001); and Bioorg. Med. Chem. Lett. 11, 1717-1721 (2001)] involving Pd-catalyzed carbonylation of the triflate 11 in the presence of ammonia and the Pd(O) ligand, DPPF ([l,l’-bis(diphenylρhosphino)ferrocene]) and DMSO.(B) Synthesis of 3-Carboxyamido-4-hydroxy-naltrexone derivative 3[030] Zinc dust (26 mg, 0.40 mmol) was added in portions to a solution of 2 (50 mg, 0.14 mmol) in HCl (37%, 0.2 mL) and AcOH (2 mL) at reflux. After heating at reflux for a further 15 min, the reaction was cooled by the addition of ice/water (10 mL) and basified (pH=9) with NH3/H2O, and the solution was extracted with EtOAc (3×10 mL). The organic extracts were washed with brine, dried, and concentrated. The residue was purified by column chromatography (SiO2, CH2Cl2, CH3OH : NH3/H2O = 15:1:0.01) to give compound 3 as a foam (25 mg, 50%). 1H NMR (CDC13) δl3.28(s, IH, 4-OH), 7.15(d, IH, J=8.1, H-2), 6.47(d, IH, J=8.4, H- 1), 6.10(br, IH, N-H), 4.35(br, IH, N-H), 4.04(dd,lH, J=I.8, 13.5, H-5), 3.11( d, IH, J=6), 2.99( d, IH, J=5.7), 2.94( s, IH), 2.86( d, IH, J= 6), 2.84-2.75(m, 2H), 2.65-2.61(m, 2H), 2.17-2.05(m, IH), 1.89-1.84(m, 2H), 0.85(m, IH), 0.56-0.50(m, 2H), 0.13-0.09(m, 2H). [α]D25= -98.4° (c=0.6, CH2Cl2). MS m/z (ESI) 371(MH+).

Paper

 Bioorg. Med. Chem. Lett. 200010, 183-187.

https://www.sciencedirect.com/science/article/abs/pii/S0960894X99006708

Abstract

Opioid binding affinities were assessed for a series of cyclazocine analogues where the prototypic 8-OH substituent of cyclazocine was replaced by amino and substituted-amino groups. For μ and κ opioid receptorssecondary amine derivatives having the (2R,6R,11R)-configuration had the highest affinity. Most targets were efficiently synthesized from the triflate of cyclazocine or its enantiomers using Pd-catalyzed amination procedures.

PAPER

Bioorg. Med. Chem. Lett. 200111, 1717-1721.

https://www.sciencedirect.com/science/article/abs/pii/S0960894X01002785

Abstract

In response to the unexpectedly high affinity for opioid receptors observed in a novel series of cyclazocine analogues where the prototypic 8-OH was replaced by a carboxamido group, we have prepared the corresponding 3-CONH2 analogues of morphine and naltrexone. High affinity (Ki=34 and 1.7 nM) for μ opioid receptors was seen, however, the new targets were 39- and 11-fold less potent than morphine and naltrexone, respectively.

Abstract

High-affinity binding to μ opioid receptors has been identified in a series of novel 3-carboxamido analogues of morphine and naltrexone.

References

  1. ^ Turncliff R, DiPetrillo L, Silverman B, Ehrich E (February 2015). “Single- and multiple-dose pharmacokinetics of samidorphan, a novel opioid antagonist, in healthy volunteers”. Clinical Therapeutics37 (2): 338–48. doi:10.1016/j.clinthera.2014.10.001PMID 25456560.
  2. ^ Wentland MP, Lu Q, Lou R, Bu Y, Knapp BI, Bidlack, JM (April 2005). “Synthesis and opioid receptor binding properties of a highly potent 4-hydroxy analogue of naltrexone”. Bioorganic & Medicinal Chemistry Letters15 (8): 2107–10. doi:10.1016/j.bmcl.2005.02.032PMID 15808478.
  3. ^ “Samidorphan”Adis Insight. Springer Nature Switzerland AG.
  4. ^ Hillemacher T, Heberlein A, Muschler MA, Bleich S, Frieling H (August 2011). “Opioid modulators for alcohol dependence”. Expert Opinion on Investigational Drugs20 (8): 1073–86. doi:10.1517/13543784.2011.592139PMID 21651459.
  5. ^ Clinical trial number NCT01366001 for “ALK33BUP-101: Safety and Pharmacodynamic Effects of ALKS 33-BUP Administered Alone and When Co-administered With Cocaine” at ClinicalTrials.gov
  6. ^ “ALKS 5461 drug found to reduce depressive symptoms in Phase 1/2 study”.
  7. ^ “Investigational ALKS 5461 Channels ‘Opium Cure’ for Depression”.
  8. ^ LaMattina J (15 January 2013). “Will Alkermes’ Antipsychotic ALKS-3831 Become Another Tredaptive?”Forbes.
  9. ^ Correll, Christoph U.; Newcomer, John W.; Silverman, Bernard; DiPetrillo, Lauren; Graham, Christine; Jiang, Ying; Du, Yangchun; Simmons, Adam; Hopkinson, Craig; McDonnell, David; Kahn, René S. (2020-08-14). “Effects of Olanzapine Combined With Samidorphan on Weight Gain in Schizophrenia: A 24-Week Phase 3 Study”American Journal of Psychiatry177 (12): 1168–1178. doi:10.1176/appi.ajp.2020.19121279ISSN 0002-953X.
  10. ^ “FDA Panel: Some Risk OK for Olanzapine Combo With Less Weight Gain”http://www.medpagetoday.com. 2020-10-09. Retrieved 2021-01-23.
  11. Jump up to:a b Linda P. Dwoskin (29 January 2014). Emerging Targets & Therapeutics in the Treatment of Psychostimulant Abuse. Elsevier Science. pp. 398–399, 402–403. ISBN 978-0-12-420177-4.
  12. Jump up to:a b Wentland MP, Lou R, Lu Q, Bu Y, Denhardt C, Jin J, et al. (April 2009). “Syntheses of novel high affinity ligands for opioid receptors”Bioorganic & Medicinal Chemistry Letters19 (8): 2289–94. doi:10.1016/j.bmcl.2009.02.078PMC 2791460PMID 19282177.
  13. ^ McElroy SL, Guerdjikova AI, Blom TJ, Crow SJ, Memisoglu A, Silverman BL, Ehrich EW (April 2013). “A placebo-controlled pilot study of the novel opioid receptor antagonist ALKS-33 in binge eating disorder”The International Journal of Eating Disorders46(3): 239–45. doi:10.1002/eat.22114PMID 23381803.

External links

 
Clinical data
Other namesALKS-33, RDC-0313; 3-Carboxamido-4-hydroxynaltrexone
Routes of
administration
Oral
Pharmacokinetic data
Elimination half-life7–9 hours[1]
Identifiers
showIUPAC name
CAS Number852626-89-2 
PubChem CID11667832
ChemSpider23259667
UNII7W2581Z5L8
KEGGD10162 
Chemical and physical data
FormulaC21H26N2O4
Molar mass370.449 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI

/////////samidorphan, サミドルファン, ALKS 33, ALKS-33, RDC-0313, RDC-0313-00, APPROVALS 2021, FDA 2021, Lybalvi

SMILESO[C@@H](CC(O)=O)C(O)=O.NC(=O)C1=CC=C2C[C@H]3N(CC4CC4)CC[C@@]4(CC(=O)CC[C@@]34O)C2=C1O

wdt-11

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Colchicine


Skeletal formula of colchicine

Colchicine

CAS Registry Number: 64-86-8CAS Name:N-[(7S)-5,6,7,9-Tetrahydro-1,2,3,10-tetramethoxy-9-oxobenzo[a]heptalen-7-yl]acetamideMolecular Formula: C22H25NO6Molecular Weight: 399.44

CSIR-Laxai Life Sciences get DCGI nod for clinical trials Colchicine on Covid patients

laxai

https://www.thehindubusinessline.com/news/csir-laxai-life-sciences-get-dcgi-nod-for-clinical-trials-colchicine-on-covid-patients/article34795126.ece?fbclid=IwAR21MOLpbdhdTR-owHYYWC-xG1DZEECOg1PcYRoMICoAwVkV7TWO2CgZQWA

It is an important therapeutic intervention for Covid-19 patients with cardiac co-morbidities and also for reducing proinflammatory cytokines

The Council of Scientific & Industrial Research (CSIR), and Laxai Life Sciences Pvt. Ltd. Hyderabad, have obtained approval from the Drug Controller General of India (DCGI) to undertake a two-arm phase-II clinical trial of the drug Colchicine for Covid-19 treatment.

The partner CSIR institutes in this important clinical trial are the CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad and CSIR-Indian Institute of Integrative Medicine (IIIM), Jammu.

According to Ram Vishwakarma, advisor to DG-CSIR, colchicine, in combination with standard of care, will be an important therapeutic intervention for Covid-19 patients with cardiac co-morbidities and also for reducing proinflammatory cytokines, leading to faster recovery.

A number of global studies have confirmed now that cardiac complications during the course of Covid-19 infections and post-covid syndrome are leading to the loss of many lives, and it is essential to look for new or repurposed drugs.

laxai

VAMI MADDIPATLA

CHAIRMAN AND MD,  LAXAI

A visionary & an entrepreneur with 17 years of experience in technology and bio-pharma industries. Founder and ex-CEO of LAXAI Pharma Ltd – a clinical data services company based in NJ, USA. Past employment: Pfizer, Wyeth Pharmaceuticals, Johnson & Johnson and Deloitte.

Vamsi provides a unique blend of operational and financial experience – along with a strong and expansive network of key influencers, industry experts and financial partners. He delivers a visionary understanding of client challenges and opportunities, and the instinctive ability to facilitate collaboration between the right people to turn strategic concepts into actionable plans – and, ultimately, into business results.

Dr S Chandrasekhar (Director CSIR-IICT, Hyderabad) and Dr. DS Reddy (Director, CSIR-IIIM, Jammu), the two partner institutes from CSIR said that they were looking forward to the outcome of this Phase II clinical efficacy trial on Colchicine, which may lead to life-saving intervention in the management of hospitalised patients.

srivari

Dr S Chandrasekhar (Director CSIR-IICT, Hyderabad)

ds-reddy

Dr. DS Reddy (Director, CSIR-IIIM, Jammu)

India is one of the largest producers of this key drug and if successful, it will be made available to the patients at an affordable cost.

According to Ram Upadhayay, CEO, Laxai the enrollment of patients has already begun at multiple sites across India and the trial is likely to be completed in the next 8-10 weeks.

The drug can be made available to the large population of India based on the results of this trial and regulatory approval, he added.

Recent clinical studies have reported in leading medical journals about colchicine being associated with a significant reduction in the rates of recurrent pericarditis, post-pericardiotomy syndrome, and peri-procedural atrial fibrillation following cardiac surgery and atrial fibrillation ablation, according to a release.

laxai

Ram Upadhayaya, PhD

Chief Executive Officer, LAXAI

Ram Upadhayaya, CEO of Laxai Life Sciences, brings with him more than two decades of R&D experience spanning both academia and industry. A Ph. D in synthetic organic Chemistry, Ram has held key positions with leading international drug discovery organizations such as Bioimics AB Sweden, and Lupin India. Apart from his industrial background, Ram has been deeply associated with academic research. He was associated with Institute of Molecular Medicine, India as Principal Scientist as well as Uppsala University, Sweden in the capacity of Assistant Professor (Forskare). During these stints he significantly contributed to the development of novel therapeutics against infectious diseases such as AIDS and TB.

Ram has 10 international patents to his credit and has authored 25 peer reviewed publications. He is concurrently a consultant to the scientific advisory committee of the Principal Scientific Advisor, Government of India.

laxai
Raghava Reddy Kethiri, PhD, LAXAI
Chief Scientific Officer

25+ years of experience at various leadership positions in Biotech, CRO and Universities; Ex Karlsruhe Institute of Technology (KIT), Technical University of Dresden (TUD), JADO Technologies , Dresden, Germany, Jubilant Biosys, India

Delivered several leads, optimised leads and PCCs/DCs across Oncology, Pain, CNS, MD and Antibacterial therapeutics areas for global pharmaceutical companies. Co-Inventor of two clinical candidates ASN-001 ( NCT 02349139) for Metastatic Castration Resistant Prostrate Cancer & ASN-007 (NCT 03415126) for metastatic KRAS, NRAS & HRAS mutated solid tumors. Co-authored over 60 publications/patents (US/EU/Indian)

Colchicine

CAS Registry Number: 64-86-8

CAS Name:N-[(7S)-5,6,7,9-Tetrahydro-1,2,3,10-tetramethoxy-9-oxobenzo[a]heptalen-7-yl]acetamideMolecular Formula: C22H25NO6Molecular Weight: 399.44Percent Composition: C 66.15%, H 6.31%, N 3.51%, O 24.03%

Literature References: A major alkaloid of Colchicum autumnale L., Liliaceae. Extraction procedure: Chemnitius, J. Prakt. Chem. [II] 118, 29 (1928); F. E. Hamerslag, Technology and Chemistry of Alkaloids (New York, 1950) pp 66-80. Structure: Dewar, Nature155, 141 (1945); King et al.,Acta Crystallogr.5, 437 (1952); Horowitz, Ullyot, J. Am. Chem. Soc.74, 487 (1952). Crystal structure: L. Lessinger, T. N. Margulis, Acta Crystallogr.B34, 578 (1978). 
Total synthesis: Schreiber et al.,Helv. Chim. Acta44, 540 (1961); Van Tamelen et al.,Tetrahedron14, 8 (1961); Nakamura, Chem. Pharm. Bull.8, 843 (1960); Sunagawa et al.,ibid.9, 81 (1961); 10, 281 (1962); Scott et al.,Tetrahedron21, 3605 (1965); Woodward, Harvey Lectures, Ser. 59 (Academic Press, New York, 1965) p 31; Kotani et al.,Chem. Commun.1974, 300; D. A. Evans et al.,J. Am. Chem. Soc.103, 5813 (1981). 
Biosynthesis: Leete, Tetrahedron Lett.1965, 333; Battersby et al.,J. Chem. Soc.1964, 4257; Hill, Unrau, Can. J. Chem.43, 709 (1965). Tubulin-binding activity: J. M. Andreu, S. N. Timasheff, Proc. Natl. Acad. Sci. USA79, 6753 (1982). Toxicity: S. J. Rosenbloom, F. C. Ferguson, Toxicol. Appl. Pharmacol.13, 50 (1968); R. P. Beliles, ibid.23, 537 (1972). Clinical evaluations in cirrhosis of the liver: M. M. Kaplan et al.,N. Engl. J. Med.315, 1448 (1986); D. Kershenobich et al.,ibid.318, 1709 (1988). Bibliography of early literature: Eigsti, Lloydia10, 65 (1947). 
Monograph: O. J. Eigsti, P. Dustin, Jr., Colchicine in Agriculture, Medicine, Biology and Chemistry (Iowa State College Press, Ames, Iowa, 1955). Reviews: Fleming, Selected Organic Syntheses (John Wiley, London, 1973) pp 183-207; G. Lagrue et al.,Ann. Med. Interne132, 496-500 (1981); F. D. Malkinson, Arch. Dermatol.118, 453-457 (1982). Comprehensive description: D. K. Wyatt et al.,Anal. Profiles Drug Subs.10, 139-182 (1981). 
Properties: Pale yellow scales or powder, mp 142-150°. Darkens on exposure to light. Has been crystallized from ethyl acetate, pale yellow needles, mp 157°. [a]D17 -429° (c = 1.72). [a]D17 -121° (c = 0.9 in chloroform). pK at 20°: 12.35; pH of 0.5% soln: 5.9. uv max (95% ethanol): 350.5, 243 nm (log e 4.22; 4.47). One gram dissolves in 22 ml water, 220 ml ether, 100 ml benzene; freely sol in alcohol or chloroform. Practically insol in petr ether. Forms two cryst compds with chloroform, B.CHCl3 or B.2CHCl3, which do not give up their chloroform unless heated between 60 and 70° for considerable time. LD50 in rats (mg/kg): 1.6 i.v. (Rosenbloom, Ferguson); in mice (mg/kg): 4.13 i.v. (Beliles).

Melting point: mp 142-150°; mp 157°pKa: pK at 20°: 12.35; pH of 0.5% soln: 5.9Optical Rotation: [a]D17 -429° (c = 1.72); [a]D17 -121° (c = 0.9 in chloroform)Absorption maximum: uv max (95% ethanol): 350.5, 243 nm (log e 4.22; 4.47)

Toxicity data: LD50 in rats (mg/kg): 1.6 i.v. (Rosenbloom, Ferguson); in mice (mg/kg): 4.13 i.v. (Beliles)Use: In research in plant genetics (for doubling chromosomes).Therap-Cat: Gout suppressant. Treatment of Familial Mediterranean Fever.Therap-Cat-Vet: Has been used as an antineoplastic.Keywords: Antigout.

SYN

DOI: 10.1039/C39740000300

DOI: 10.1002/hlca.19610440225 DOI: 10.1021/ja00409a032

http://www.druglead.com/cds/Colchicine.html

File:Colchicine synthesis.svg

SYN

https://pubs.rsc.org/en/content/articlelanding/2017/sc/c7sc01341h#!divAbstract

Here, we describe a concise, enantioselective, and scalable synthesis of (−)-colchicine (9.2% overall yield, >99% ee). Moreover, we have also achieved the first syntheses of (+)-demecolcinone and metacolchicine, and determined their absolute configurations. The challenging tricyclic 6-7-7 core of colchicinoids was efficiently introduced using an intramolecular oxidopyrylium-mediated [5 + 2] cycloaddition reaction. Notably, the synthesized colchicinoid 23 exhibited potent inhibitory activity toward the cell growth of human cancer cell lines (IC50 = ∼3.0 nM), and greater inhibitory activity towards microtubule assembly than colchicine, making it a promising lead in the search for novel anticancer agents.

Graphical abstract: Enantioselective total synthesis of (−)-colchicine, (+)-demecolcinone and metacolchicine: determination of the absolute configurations of the latter two alkaloids

Enantioselective total synthesis of (−)- and (+)-colchicine

The synthesis began with the transition-metal-catalyzed C–H bond functionalization of 7 with 14 (Scheme 1). Inspired by Li’s seminal work,18 we applied the strategy to compound 7. Pleasingly, after optimization, we successfully generated the N-sulfonyl imine in situ by reaction of 7 with TsNH2 (15) in the presence of anhydrous CuSO4 in THF. Furthermore, subsequent treatment of this imine with [RhCp*Cl2]2 (1 mol%), AgSbF6 (4 mol%), NaOAc (2.0 equiv.), and 14 (2.0 equiv.) at 80 °C afforded ortho-olefinated benzaldehyde 16 in good yield (90% on a 0.5 g scale; 70% on a 5.0 g scale). This modified catalytic C–H bond activation involved a transient directing group.19

Scheme 1 Enantioselective synthesis of (−)-colchicine and (+)-colchicine.

SYN

https://chemistry.stackexchange.com/questions/67473/synthesis-of-colchicine

Recently one of my relatives have fallen ill and was prescribed with some colchicine. Looking at the structure of the molecule, and with nothing much to do, I decided to put my retrosynthetic skills to the test. Here is a picture of my thought process: 

Is there a better way to design a synthesis for this compound using the disconnection method.

From 11b, a Birch reduction is carried out to give the qunione 10b. A rearrangement of the ketone with methanediazonium gives 9b. A dihydroxylation with a peroxy acid and subsequent addition of water gives 8b. A double dehydration reaction with sulfuric acid, coupled with the protection of the ketone with propan-1,3-diol gives the seven-membered quinone 7b. A Heck reaction (or Ullmann reaction) with 7a with a palladium catalyst yields 6. (The protection group is thereafter labelled “PG”) Friedel-Crafts acylation with ethanoyl chloride yields 5 (although on second thoughts, I should have done the acylation from 7a from the start). A Michael addition is then carried out with BuLiBuLi to lithiate the ketone to give the terminal imine 4. Since this terminal imine is unstable, a mild reducing agent converts the imine to the amine 3. The ketone is then removed by addition of dithiol and subsequently reduced by Raney nickel to form 2. Finally, a simple condensation reaction between the amine and acetic anhydride, followed by deprotection of the ketone using an acid, yields the final product colchicine, 1.

Colchicine is a medication used to treat gout[1][2] and Behçet’s disease.[3] In gout, it is less preferred to NSAIDs or steroids.[1] Other uses for colchicine include the management of pericarditis and familial Mediterranean fever.[1][4] Colchicine is taken by mouth.[1]

Colchicine has a narrow therapeutic index and overdosing is therefore a significant risk. Common side effects of colchicine include gastrointestinal upset, particularly at high doses.[5] Severe side effects may include low blood cells and rhabdomyolysis, and the medication can be deadly in overdose.[1] It is not clear whether colchicine is safe for use during pregnancy, but its use during breastfeeding appears to be safe.[1][6] Colchicine works by decreasing inflammation via multiple mechanisms.[7]

Colchicine, in the form of the autumn crocus (Colchicum autumnale), has been used as early as 1500 BC to treat joint swelling.[8] It was approved for medical use in the United States in 1961.[9] It is available as a generic medication in the United Kingdom.[6] In 2017, it was the 201st-most commonly prescribed medication in the United States, with more than two million prescriptions.[10][11]

Medical uses

Gout

Colchicine is an alternative for those unable to tolerate NSAIDs in gout.[12] At high doses, side effects (primarily gastrointestinal upset) limit its use.[13][14] At lower doses, it is well tolerated.[13][15][16][17] One review found low-quality evidence that low-dose colchicine (1.8 mg in one hour or 1.2 mg per day) reduced gout symptoms and pain, whereas high-dose colchicine (4.8 mg over 6 hours) was effective against pain, but caused more severe side effects, such as diarrhea, nausea or vomiting.[16]

For treating gout symptoms, colchicine is used orally with or without food, as symptoms first appear.[18] Subsequent doses may be needed if symptoms worsen.[18][16] There is preliminary evidence that daily colchicine (0.6 mg twice daily) was effective as a long-term prophylaxis when used with allopurinol to reduce the risk of increased uric acid levels and acute gout flares,[2] although adverse gastrointestinal effects may occur.[19]

Other conditions

Colchicine is also used as an anti-inflammatory agent for long-term treatment of Behçet’s disease.[20] It appears to have limited effect in relapsing polychondritis, as it may only be useful for the treatment of chondritis and mild skin symptoms.[21] It is a component of therapy for several other conditions, including pericarditis, pulmonary fibrosis, biliary cirrhosis, various vasculitides, pseudogout, spondyloarthropathies, calcinosis, scleroderma, and amyloidosis.[20][22][23] Research regarding the efficacy of colchicine in many of these diseases has not been performed.[23] It is also used in the treatment of familial Mediterranean fever,[20] in which it reduces attacks and the long-term risk of amyloidosis.[24]

Colchicine is effective for prevention of atrial fibrillation after cardiac surgery.[25] Potential applications for the anti-inflammatory effect of colchicine have been studied with regard to atherosclerosis and chronic coronary disease (e.g., stable ischemic heart disease).[26] In people with recent myocardial infarction (recent heart attack), it has been found to reduce risk of future cardiovascular events. Its clinical use may grow to include this indication.[27][28]

Colchicine is also being studied in clinical trials for possible effects on COVID-19.[29][30]

Contraindications

Long-term (prophylactic) regimens of oral colchicine are absolutely contraindicated in people with advanced kidney failure (including those on dialysis).[18] About 10-20 percent of a colchicine dose is excreted unchanged by the kidneys; it is not removed by hemodialysis. Cumulative toxicity is a high probability in this clinical setting, and a severe neuromyopathy may result. The presentation includes a progressive onset of proximal weakness, elevated creatine kinase, and sensorimotor polyneuropathy. Colchicine toxicity can be potentiated by the concomitant use of cholesterol-lowering drugs.[18]

Adverse effects

Deaths – both accidental and intentional – have resulted from overdose of colchicine.[18] Typical side effects of moderate doses may include gastrointestinal upset, diarrhea, and neutropenia.[13] High doses can also damage bone marrow, lead to anemia, and cause hair loss. All of these side effects can result from inhibition of mitosis,[31] which may include neuromuscular toxicity and rhabdomyolysis.[18]

Toxicity

According to one review, colchicine poisoning by overdose (range of acute doses of 7 to 26 mg) begins with a gastrointestinal phase occurring 10–24 hours after ingestion, followed by multiple organ dysfunction occurring 24 hours to 7 days after ingestion, after which the affected person either declines into multi-organ failure or recovers over several weeks.[32]

Colchicine can be toxic when ingested, inhaled, or absorbed in the eyes.[13] Colchicine can cause a temporary clouding of the cornea and be absorbed into the body, causing systemic toxicity. Symptoms of colchicine overdose start 2 to 24 hours after the toxic dose has been ingested and include burning in the mouth and throat, fevervomitingdiarrhea, and abdominal pain.[18] This can cause hypovolemic shock due to extreme vascular damage and fluid loss through the gastrointestinal tract, which can be fatal.[32][33]

If the affected person survives the gastrointestinal phase of toxicity, they may experience multiple organ failure and critical illness. This includes kidney damage, which causes low urine output and bloody urinelow white blood cell counts that can last for several days; anemia; muscular weakness; liver failurehepatomegalybone marrow suppressionthrombocytopenia; and ascending paralysis leading to potentially fatal respiratory failure. Neurologic symptoms are also evident, including seizuresconfusion, and delirium; children may experience hallucinations. Recovery may begin within six to eight days and begins with rebound leukocytosis and alopecia as organ functions return to normal.[32][31]

Long-term exposure to colchicine can lead to toxicity, particularly of the bone marrowkidney, and nerves. Effects of long-term colchicine toxicity include agranulocytosis, thrombocytopenia, low white blood cell counts, aplastic anemia, alopecia, rashpurpuravesicular dermatitiskidney damageanuriaperipheral neuropathy, and myopathy.[31]

No specific antidote for colchicine is known, but supportive care is used in cases of overdose. In the immediate period after an overdose, monitoring for gastrointestinal symptoms, cardiac dysrhythmias, and respiratory depression is appropriate,[31] and may require gastrointestinal decontamination with activated charcoal or gastric lavage.[32][33]

Mechanism of toxicity

With overdoses, colchicine becomes toxic as an extension of its cellular mechanism of action via binding to tubulin.[32] Cells so affected undergo impaired protein assembly with reduced endocytosisexocytosiscellular motility, and interrupted function of heart cells, culminating in multi-organ failure.[7][32]

Epidemiology

In the United States, there are several hundred recorded cases of colchicine toxicity annually; approximately 10% of which end with serious morbidity or mortality. Many of these cases are intentional overdoses, but others were accidental; for example, if the drug was not dosed appropriately for kidney function. Most cases of colchicine toxicity occur in adults. Many of these adverse events resulted from the use of intravenous colchicine.[23]

Drug interactions

Colchicine interacts with the P-glycoprotein transporter, and the CYP3A4 enzyme involved in drug and toxin metabolism.[18][32] Fatal drug interactions have occurred when colchicine was taken with other drugs that inhibit P-glycoprotein and CYP3A4, such as erythromycin or clarithromycin.[18]

People taking macrolide antibioticsketoconazole or cyclosporine, or those who have liver or kidney disease, should not take colchicine, as these drugs and conditions may interfere with colchicine metabolism and raise its blood levels, potentially increasing its toxicity abruptly.[18][32] Symptoms of toxicity include gastrointestinal upset, fever, muscle painlow blood cell counts, and organ failure.[13][18] People with HIV/AIDS taking atazanavirdarunavirfosamprenavirindinavirlopinavirnelfinavirritonavir, or saquinavir may experience colchicine toxicity.[18] Grapefruit juice and statins can also increase colchicine concentrations.[18]

In gout, inflammation in joints results from the precipitation of circulating uric acid, exceeding its solubility in blood and depositing as crystals of monosodium urate in and around synovial fluid and soft tissues of joints.[7] These crystal deposits cause inflammatory arthritis, which is initiated and sustained by mechanisms involving various proinflammatory mediators, such as cytokines.[7] Colchicine accumulates in white blood cells and affects them in a variety of ways: decreasing motility, mobilization (especially chemotaxis) and adhesion.[23]

Under preliminary research are various mechanisms by which colchicine may interfere with gout inflammation:

Generally, colchicine appears to inhibit multiple proinflammatory mechanisms, while enabling increased levels of anti-inflammatory mediators.[7] Apart from inhibiting mitosis, colchicine inhibits neutrophil motility and activity, leading to a net anti-inflammatory effect, which has efficacy for inhibiting or preventing gout inflammation.[7][18]

The plant source of colchicine, the autumn crocus (Colchicum autumnale), was described for treatment of rheumatism and swelling in the Ebers Papyrus (circa 1500 BC), an Egyptian medical papyrus.[34] It is a toxic alkaloid and secondary metabolite.[13][35][18] Colchicum extract was first described as a treatment for gout in De Materia Medica by Pedanius Dioscorides, in the first century AD. Use of the bulb-like corms of Colchicum to treat gout probably dates to around 550 AD, as the “hermodactyl” recommended by Alexander of TrallesColchicum corms were used by the Persian physician Avicenna, and were recommended by Ambroise Paré in the 16th century, and appeared in the London Pharmacopoeia of 1618.[36][23] Colchicum use waned over time, likely due to the severe gastrointestinal side effects preparations caused. In 1763, Colchicum was recorded as a remedy for dropsy (now called edema) among other illnesses.[23] Colchicum plants were brought to North America by Benjamin Franklin, who had gout himself and had written humorous doggerel about the disease during his stint as United States Ambassador to France.[37]

Colchicine was first isolated in 1820 by the French chemists P. S. Pelletier and J. B.Caventou.[38] In 1833, P. L. Geiger purified an active ingredient, which he named colchicine.[39] It quickly became a popular remedy for gout.[23] The determination of colchicine’s structure required decades, although in 1945, Michael Dewar made an important contribution when he suggested that, among the molecule’s three rings, two were seven-member rings.[40] Its pain-relieving and anti-inflammatory effects for gout were linked to its ability to bind with tubulin.

An unintended consequence of the 2006 U.S. Food and Drug Administration (FDA) safety program called the Unapproved Drugs Initiative—through which the FDA sought more rigorous testing of efficacy and safety of colchicine and other unapproved drugs[41]—was a price increase of 2000 percent [42] for “a gout remedy so old that the ancient Greeks knew about its effects.”[42] Under Unapproved Drugs Initiative small companies like URL Pharma, a Philadelphia drugmaker, were rewarded with licenses for testing of medicines like colchicine. In 2009, the FDA reviewed a New Drug Application for colchicine submitted by URL Pharma. URL Pharma did the testing, gained FDA formal approval, and was granted rights over colchicine. With this monopoly pricing power, the price of colchicine increased.

In 2012 Asia’s biggest drugmaker, Takeda Pharmaceutical Co., acquired URL Pharma for $800 million including the rights to colchicine (brand name Colcrys) earning $1.2 billion in revenue by raising the price even more.[42]

Oral colchicine had been used for many years as an unapproved drug with no FDA-approved prescribing information, dosage recommendations, or drug interaction warnings.[43] On July 30, 2009, the FDA approved colchicine as a monotherapy for the treatment of three different indications (familial Mediterranean fever, acute gout flares, and for the prophylaxis of gout flares[43]), and gave URL Pharma a three-year marketing exclusivity agreement[44] in exchange for URL Pharma doing 17 new studies and investing $100 million into the product, of which $45 million went to the FDA for the application fee. URL Pharma raised the price from $0.09 per tablet to $4.85, and the FDA removed the older unapproved colchicine from the market in October 2010, both in oral and intravenous forms, but allowed pharmacies to buy up the older unapproved colchicine.[45] Colchicine in combination with probenecid has been FDA-approved before 1982.[44]

July 29, 2009, colchicine won FDA approval in the United States as a stand-alone drug for the treatment of acute flares of gout and familial Mediterranean fever.[46][47] It had previously been approved as an ingredient in an FDA-approved combination product for gout. The approval was based on a study in which two doses (1.2 mg and 0.6 mg) an hour apart were as effective as higher doses in combating the acute flare of gout.[17]

As a drug antedating the FDA, colchicine was sold in the United States for many years without having been reviewed by the FDA for safety and efficacy. The FDA reviewed approved colchicine for gout flares, awarding Colcrys a three-year term of market exclusivity, prohibiting generic sales, and increasing the price of the drug from $0.09 to $4.85 per tablet.[48][49][50]

Numerous consensus guidelines, and previous randomized controlled trials, had concluded that colchicine is effective for acute flares of gouty arthritis. However, as of 2006, the drug was not formally approved by the FDA, owing to the lack of a conclusive randomized control trial (RCT). Through the Unapproved Drugs Initiative, the FDA sought more rigorous testing of the efficacy and safety of colchicine and other unapproved drugs.[41] In exchange for paying for the costly testing, the FDA gave URL Pharma three years of market exclusivity for its Colcrys brand,[51] under the Hatch-Waxman Act, based in part on URL-funded research in 2007, including pharmacokinetic studies and a randomized control trial with 185 patients with acute gout.

In April 2010, an editorial in the New England Journal of Medicine said that the rewards of this legislation are not calibrated to the quality or value of the information produced, that no evidence of meaningful improvement to public health was seen, and that it would be less expensive for the FDA, the National Institutes of Health or large insurers to pay for trials themselves. Furthermore, the cost burden of this subsidy falls primarily on patients or their insurers.[52] In September 2010, the FDA ordered a halt to marketing unapproved single-ingredient oral colchicine.[53]

Colchicine patents expire on February 10, 2029.[54]

URL Pharma also received seven years of market exclusivity for Colcrys in the treatment of familial Mediterranean fever, under the Orphan Drug Law. URL Pharma then raised the price per tablet from $0.09 to $4.85 and sued to remove other versions from the market, increasing annual costs for the drug to U.S. state Medicaid programs from $1 million to $50 million. Medicare also paid significantly higher costs, making this a direct money-loser for the government. (In a similar case, thalidomide was approved in 1998 as an orphan drug for leprosy and in 2006 for multiple myeloma.)[52]

Regulation

It is classified as an extremely hazardous substance in the United States as defined in Section 302 of the U.S. Emergency Planning and Community Right-to-Know Act (42 U.S.C. 11002) and is subject to strict reporting requirements by facilities which produce, store, or use it in significant quantities.[55]

Formulations and dosing

Trade names for colchicine are Colcrys or Mitigare which are manufactured as a dark– and light-blue capsule having a dose of 0.6 mg.[18][56] Colchicine is also prepared as a white, yellow, or purple pill (tablet) having a dose of 0.6 mg.[56]

Colchicine is typically prescribed to mitigate or prevent the onset of gout, or its continuing symptoms and pain, using a low-dose prescription of 0.6 to 1.2 mg per day, or a high-dose amount of up to 4.8 mg in the first 6 hours of a gout episode.[5][18][16] With an oral dose of 0.6 mg, peak blood levels occur within one to two hours.[35] For treating gout, the initial effects of colchicine occur in a window of 12 to 24 hours, with a peak within 48 to 72 hours.[18] It has a narrow therapeutic window, requiring monitoring of the subject for potential toxicity.[18] Colchicine is not a general pain relief drug, and is not used to treat pain in other disorders.[18]

Biosynthesis

According to laboratory research, the biosynthesis of colchicine involves the amino acids phenylalanine and tyrosine as precursors. Giving radioactive phenylalanine-2-14C to C. byzantinum, another plant of the family Colchicaceae, resulted in its incorporation into colchicine.[57] However, the tropolone ring of colchicine resulted from the expansion of the tyrosine ring. Radioactive feeding experiments of C. autumnale revealed that colchicine can be synthesized biosynthetically from (S)-autumnaline. That biosynthesic pathway occurs primarily through a phenolic coupling reaction involving the intermediate isoandrocymbine. The resulting molecule undergoes O-methylation directed by S-adenosylmethionine. Two oxidation steps followed by the cleavage of the cyclopropane ring leads to the formation of the tropolone ring contained by N-formyldemecolcine. N-formyldemecolcine hydrolyzes then to generate the molecule demecolcine, which also goes through an oxidative demethylation that generates deacetylcolchicine. The molecule of colchicine appears finally after addition of acetyl-coenzyme A to deacetylcolchicine.[58][59]

A

Purification

Colchicine may be purified from Colchicum autumnale (autumn crocus) or Gloriosa superba (glory lily). Concentrations of colchicine in C. autumnale peak in the summer, and range from 0.1% in the flower to 0.8% in the bulb and seeds.[23]

Colchicine is widely used in plant breeding by inducing polyploidy in plant cells to produce new or improved varieties, strains and cultivars.[60] When used to induce polyploidy in plants, colchicine cream is usually applied to a growth point of the plant, such as an apical tip, shoot, or sucker. Seeds can be presoaked in a colchicine solution before planting. Since chromosome segregation is driven by microtubules, colchicine alters cellular division by inhibiting chromosome segregation during meiosis; half the resulting gametes, therefore, contain no chromosomes, while the other half contains double the usual number of chromosomes (i.e., diploid instead of haploid, as gametes usually are), and lead to embryos with double the usual number of chromosomes (i.e., tetraploid instead of diploid).[60] While this would be fatal in most higher animal cells, in plant cells it is not only usually well-tolerated, but also frequently results in larger, hardier, faster-growing, and in general more desirable plants than the normally diploid parents. For this reason, this type of genetic manipulation is frequently used in breeding plants commercially.[60]

When such a tetraploid plant is crossed with a diploid plant, the triploid offspring are usually sterile (unable to produce fertile seeds or spores), although many triploids can be propagated vegetatively. Growers of annual triploid plants not readily propagated vegetatively cannot produce a second-generation crop from the seeds (if any) of the triploid crop and need to buy triploid seed from a supplier each year. Many sterile triploid plants, including some trees, and shrubs, are becoming increasingly valued in horticulture and landscaping because they do not become invasive species and will not drop undesirable fruit and seed litter. In certain species, colchicine-induced triploidy has been used to create “seedless” fruit, such as seedless watermelons (Citrullus lanatus). Since most triploids do not produce pollen themselves, such plants usually require cross-pollination with a diploid parent to induce seedless fruit production.

The ability of colchicine to induce polyploidy can be also exploited to render infertile hybrids fertile, for example in breeding triticale (× Triticosecale) from wheat (Triticum spp.) and rye (Secale cereale). Wheat is typically tetraploid and rye diploid, with their triploid hybrid infertile; treatment of triploid triticale with colchicine gives fertile hexaploid triticale.[61]

References

  1. Jump up to:a b c d e f “Colchicine Monograph for Professionals”Drugs.com. American Society of Health-System Pharmacists. Retrieved 27 March 2019.
  2. Jump up to:a b Shekelle PG, Newberry SJ, FitzGerald JD, Motala A, O’Hanlon CE, Tariq A, et al. (January 2017). “Management of Gout: A Systematic Review in Support of an American College of Physicians Clinical Practice Guideline”Annals of Internal Medicine166 (1): 37–51. doi:10.7326/M16-0461PMID 27802478.
  3. ^ Schachner LA, Hansen RC (2011). Pediatric Dermatology E-Book. Elsevier Health Sciences. p. 177. ISBN 9780723436652.
  4. ^ Hutchison, Stuart J. (2009). Pericardial Diseases: Clinical Diagnostic Imaging Atlas with DVD. Elsevier Health Sciences. p. 58. ISBN 9781416052746.
  5. Jump up to:a b “Colchicine for acute gout: updated information about dosing and drug interactions”. National Prescribing Service, Australia. 14 May 2010. Archived from the original on 30 June 2012. Retrieved 14 May 2010.
  6. Jump up to:a b British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 1085–1086. ISBN 9780857113382.
  7. Jump up to:a b c d e f g h i j Dalbeth N, Lauterio TJ, Wolfe HR (October 2014). “Mechanism of action of colchicine in the treatment of gout”Clinical Therapeutics36 (10): 1465–79. doi:10.1016/j.clinthera.2014.07.017PMID 25151572.
  8. ^ Wall, Wilson John (2015). The Search for Human Chromosomes: A History of Discovery. Springer. p. 88. ISBN 9783319263366.
  9. ^ “Colchicine capsule”DailyMed. Retrieved 27 March 2019.
  10. ^ “The Top 300 of 2020”ClinCalc. Retrieved 11 April 2020.
  11. ^ “Colchicine – Drug Usage Statistics”ClinCalc. Retrieved 11 April 2020.
  12. ^ Chen LX, Schumacher HR (October 2008). “Gout: an evidence-based review”. Journal of Clinical Rheumatology14 (5 Suppl): S55-62. doi:10.1097/RHU.0b013e3181896921PMID 18830092.
  13. Jump up to:a b c d e f “Colcrys (colchicine, USP) tablets 0.6 mg. Drug Approval Package”. US Food and Drug Administration. 17 February 2010. Retrieved 19 August 2018.
  14. ^ “Information for Healthcare Professionals: New Safety Information for Colchicine (marketed as Colcrys)”U.S. Food and Drug Administration.
  15. ^ Laubscher T, Dumont Z, Regier L, Jensen B (December 2009). “Taking the stress out of managing gout”Canadian Family Physician55 (12): 1209–12. PMC 2793228PMID 20008601.
  16. Jump up to:a b c d van Echteld I, Wechalekar MD, Schlesinger N, Buchbinder R, Aletaha D (August 2014). “Colchicine for acute gout”. The Cochrane Database of Systematic Reviews8 (8): CD006190. doi:10.1002/14651858.CD006190.pub2PMID 25123076.
  17. Jump up to:a b Terkeltaub RA, Furst DE, Bennett K, Kook KA, Crockett RS, Davis MW (April 2010). “High versus low dosing of oral colchicine for early acute gout flare: Twenty-four-hour outcome of the first multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-comparison colchicine study”. Arthritis and Rheumatism62 (4): 1060–8. doi:10.1002/art.27327PMID 20131255.
  18. Jump up to:a b c d e f g h i j k l m n o p q r s t u v “Colchicine”. Drugs.com. 1 January 2017. Retrieved 19 August 2018.
  19. ^ Qaseem A, Harris RP, Forciea MA (January 2017). “Management of Acute and Recurrent Gout: A Clinical Practice Guideline From the American College of Physicians”Annals of Internal Medicine166 (1): 58–68. doi:10.7326/M16-0570PMID 27802508.
  20. Jump up to:a b c Cocco G, Chu DC, Pandolfi S (December 2010). “Colchicine in clinical medicine. A guide for internists”. European Journal of Internal Medicine21 (6): 503–8. doi:10.1016/j.ejim.2010.09.010PMID 21111934.
  21. ^ Puéchal X, Terrier B, Mouthon L, Costedoat-Chalumeau N, Guillevin L, Le Jeunne C (March 2014). “Relapsing polychondritis”. Joint Bone Spine81 (2): 118–24. doi:10.1016/j.jbspin.2014.01.001PMID 24556284.
  22. ^ Alabed S, Cabello JB, Irving GJ, Qintar M, Burls A (August 2014). “Colchicine for pericarditis” (PDF). The Cochrane Database of Systematic Reviews8 (8): CD010652. doi:10.1002/14651858.CD010652.pub2PMID 25164988.
  23. Jump up to:a b c d e f g h i j Goldfrank’s toxicologic emergencies. Nelson, Lewis, 1963- (Eleventh ed.). New York. 2019-04-11. ISBN 978-1-259-85961-8OCLC 1020416505.
  24. ^ Portincasa P (2016). “Colchicine, Biologic Agents and More for the Treatment of Familial Mediterranean Fever. The Old, the New, and the Rare”. Current Medicinal Chemistry23 (1): 60–86. doi:10.2174/0929867323666151117121706PMID 26572612.
  25. ^ Lennerz C, Barman M, Tantawy M, Sopher M, Whittaker P (December 2017). “Colchicine for primary prevention of atrial fibrillation after open-heart surgery: Systematic review and meta-analysis” (PDF). International Journal of Cardiology249: 127–137. doi:10.1016/j.ijcard.2017.08.039PMID 28918897.
  26. ^ Malik, Jahanzeb; Javed, Nismat; Ishaq, Uzma; Khan, Umar; Laique, Talha (17 May 2020). “Is There a Role for Colchicine in Acute Coronary Syndromes? A Literature Review”Cureus12(5): e8166. doi:10.7759/cureus.8166PMC 7296886PMID 32550081.
  27. ^ Imazio M, Andreis A, Brucato A, Adler Y, De Ferrari GM (July 2020). “Colchicine for acute and chronic coronary syndromes”. Heart106 (20): heartjnl–2020–317108. doi:10.1136/heartjnl-2020-317108PMID 32611559S2CID 220305546.
  28. ^ Nidorf SM, Fiolet AT, Mosterd A, Eikelboom JW, Schut A, Opstal TS, et al. (August 2020). “Colchicine in Patients with Chronic Coronary Disease”. The New England Journal of Medicine383(19): 1838–1847. doi:10.1056/NEJMoa2021372PMID 32865380.
  29. ^ Kaul S, Gupta M, Bandyopadhyay D, Hajra A, Deedwania P, Roddy E, et al. (December 2020). “Gout Pharmacotherapy in Cardiovascular Diseases: A Review of Utility and Outcomes”American Journal of Cardiovascular Drugs : Drugs, Devices, and Other Interventionsdoi:10.1007/s40256-020-00459-1PMC 7768268PMID 33369719.
  30. ^ Reyes, Aaron Z; Hu, Kelly A; Teperman, Jacob; Wampler Muskardin, Theresa L; Tardif, Jean-Claude; Shah, Binita; Pillinger, Michael H (2020-12-08). “Anti-inflammatory therapy for COVID-19 infection: the case for colchicine”Annals of the Rheumatic Diseases: annrheumdis–2020–219174. doi:10.1136/annrheumdis-2020-219174ISSN 0003-4967PMID 33293273.
  31. Jump up to:a b c d “CDC – The Emergency Response Safety and Health Database: Biotoxin: Cochicine”. Centers for Disease Control and Prevention, US Department of Health and Human Services. Retrieved 31 December 2015.
  32. Jump up to:a b c d e f g h Finkelstein Y, Aks SE, Hutson JR, Juurlink DN, Nguyen P, Dubnov-Raz G, et al. (June 2010). “Colchicine poisoning: the dark side of an ancient drug”. Clinical Toxicology48 (5): 407–14. doi:10.3109/15563650.2010.495348PMID 20586571S2CID 33905426.
  33. Jump up to:a b Matt Doogue (2014). “Colchicine – extremely toxic in overdose” (PDF). Christchurch and Canterbury District Health Board, New Zealand. Retrieved 23 August 2018.
  34. ^ Graham W, Roberts JB (March 1953). “Intravenous colchicine in the management of gouty arthritis”Annals of the Rheumatic Diseases12 (1): 16–9. doi:10.1136/ard.12.1.16PMC 1030428PMID 13031443.
  35. Jump up to:a b “Colcrys (colchicine). Summary review for regulatory action”(PDF). Center for Drug Evaluation and Research, US Food and Drug Administration. 30 July 2009. Retrieved 19 August 2018.
  36. ^ Hartung EF (September 1954). “History of the use of colchicum and related medicaments in gout; with suggestions for further research”Annals of the Rheumatic Diseases13 (3): 190–200. doi:10.1136/ard.13.3.190PMC 1006735PMID 13198053.(free BMJ registration required)
  37. ^ Ebadi MS (2007). Pharmacodynamic basis of herbal medicineISBN 978-0-8493-7050-2.
  38. ^ Pelletier and Caventou (1820) “Examen chimique des plusieurs végétaux de la famille des colchicées, et du principe actif qu’ils renferment. [Cévadille (veratrum sabadilla); hellébore blanc (veratrum album); colchique commun (colchicum autumnale)]”(Chemical examination of several plants of the meadow saffron family, and of the active principle that they contain.) Annales de Chimie et de Physique14 : 69-81.
  39. ^ Geiger, Ph. L. (1833) “Ueber einige neue giftige organische Alkalien” (On some new poisonous organic alkalis) Annalen der Pharmacie7 (3) : 269-280; colchicine is discussed on pages 274-276.
  40. ^ Dewar MJ (February 3, 1945). “Structure of colchicine”. Letters to Editor. Nature155 (3927): 141–142. Bibcode:1945Natur.155..141Ddoi:10.1038/155141d0S2CID 4074312. Dewar did not prove the structure of colchicine; he merely suggested that it contained two seven-membered rings. Colchicine’s structure was determined by X-ray crystallography in 1952 King MV, de Vries JL, Pepinsky R (July 1952). “An x-ray diffraction determination of the chemical structure of colchicine”Acta Crystallographica5 (4): 437–440. doi:10.1107/S0365110X52001313. Its total synthesis was first accomplished in 1959 Eschenmoser A (1959). “Synthese des Colchicins”. Angewandte Chemie71 (20): 637–640. doi:10.1002/ange.19590712002.
  41. Jump up to:a b “FDA Unapproved Drugs Initiative”.
  42. Jump up to:a b c Langreth R, Koons C (6 October 2015). “2,000% Drug Price Surge Is a Side Effect of FDA Safety Program”. Bloomberg. Retrieved 27 October 2015.
  43. Jump up to:a b “FDA Approves Colchicine With Drug Interaction and Dose Warnings”. July 2009.
  44. Jump up to:a b “Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations”fda.gov.
  45. ^ “Questions and Answers for Patients and Healthcare Providers Regarding Single-ingredient Oral Colchicine Products”fda.gov.
  46. ^ “FDA Approves Gout Treatment After Long Years of Use”medpagetoday.com. 3 August 2009. Archived from the original on 5 August 2009. Retrieved 3 August 2009.
  47. ^ Cerquaglia C, Diaco M, Nucera G, La Regina M, Montalto M, Manna R (February 2005). “Pharmacological and clinical basis of treatment of Familial Mediterranean Fever (FMF) with colchicine or analogues: an update”Current Drug Targets. Inflammation and Allergy4 (1): 117–24. doi:10.2174/1568010053622984PMID 15720245. Archived from the original on 2008-12-11. Retrieved 2019-07-06.
  48. ^ Karst KR (21 October 2009). “California Court Denies Preliminary Injunction in Lanham Act Case Concerning Unapproved Colchicine Drugs”.
  49. ^ Meyer H (29 December 2009). “The High Price of FDA Approval”The Philadelphia Inquirer – via Kaiser Health News.
  50. ^ Colcrys vs. Unapproved Colchicine Statement from URL Pharma
  51. ^ “About Colcrys”Colcrys. URL Pharma. Retrieved 11 September 2011.
  52. Jump up to:a b Kesselheim AS, Solomon DH (June 2010). “Incentives for drug development–the curious case of colchicine”. The New England Journal of Medicine362 (22): 2045–7. doi:10.1056/NEJMp1003126PMID 20393164.
  53. ^ “FDA orders halt to marketing of unapproved single-ingredient oral colchicine”. 30 September 2010.
  54. ^ “Generic Colcrys Availability”drugs.com.
  55. ^ “40 CFR Appendix A to Part 355, The List of Extremely Hazardous Substances and Their Threshold Planning Quantities”LII / Legal Information Institute. Retrieved 2018-03-11.
  56. Jump up to:a b “Colchicine images”. Drugs.com. 6 August 2018. Retrieved 21 August 2018.
  57. ^ Leete E (1963). “The biosynthesis of the alkaloids of Colchicum: The incorporation of phenylalaline-2-C14 into colchicine and demecolcine”. J. Am. Chem. Soc85 (22): 3666–3669. doi:10.1021/ja00905a030.
  58. ^ Herbert, Richard B. (2001). “The biosynthesis of plant alkaloids and nitrogenous microbial metabolites”. Nat. Prod. Rep18 (1): 50–65. doi:10.1039/A809393HPMID 11245400.
  59. ^ Dewick PM (2009). Medicinal natural products: A biosynthetic approach. Wiley. pp. 360–362.
  60. Jump up to:a b c Griffiths AJF, Gelbart WM, Miller JH (1999). Modern Genetic Analysis: Changes in Chromosome Number. W. H. Freeman, New York.
  61. ^ Derman H, Emsweller SL. “The use of colchicine in plant breeding”archive.org. Retrieved 26 April 2016.

Further reading

  • Dowd, Matthew J. (April 30, 1998). “Colchicine”. Virginia Commonwealth University. Archived from the original on 2010-06-10.
  • EXT LINKS
Clinical data
Trade namesColcrys, Mitigare, others
AHFS/Drugs.comMonograph
MedlinePlusa682711
License dataUS DailyMedColchicine
Pregnancy
category
AU: D
Routes of
administration
By mouth
ATC codeM04AC01 (WHO)
Legal status
Legal statusAU: S4 (Prescription only)CA℞-onlyUK: POM (Prescription only)US: ℞-only
Pharmacokinetic data
Bioavailability45%
Protein binding35-44%
MetabolismMetabolism, partly by CYP3A4
Elimination half-life26.6-31.2 hours
ExcretionFaeces (65%)
Identifiers
showIUPAC name
CAS Number64-86-8 
PubChem CID6167
IUPHAR/BPS2367
DrugBankDB01394 
ChemSpider5933 
UNIISML2Y3J35T
KEGGD00570 
ChEBICHEBI:27882 
ChEMBLChEMBL107 
CompTox Dashboard (EPA)DTXSID5024845 DTXSID20274387, DTXSID5024845 
ECHA InfoCard100.000.544 
Chemical and physical data
FormulaC22H25NO6
Molar mass399.437 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI
  (verify)

///////////Colchicine, CSIR, Laxai Life Sciences, DCGI, clinical trials,  Covid patients, covid 19, corona virus 

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Piflufolastat F 18 injection, Dcfpyl F-18


Dcfpyl F-18.png
ChemSpider 2D Image | N-{[(1S)-1-Carboxy-5-({[6-(~18~F)fluoro-3-pyridinyl]carbonyl}amino)pentyl]carbamoyl}-L-glutamic acid | C18H2318FN4O8
img

Piflufolastat F 18 injection

Dcfpyl F-18

CAS 207181-29-0

PLAIN F 1423758-00-2  WITHOUT RADIO LABELC18 H23 F N4 O8, 441.4L-Glutamic acid, N-[[[(1S)-1-carboxy-5-[[[6-(fluoro-18F)-3-pyridinyl]carbonyl]amino]pentyl]amino]carbonyl]-2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)­ amino]-pentyl}ureido)-pentanedioic acid

Other Names

  • N-[[[(1S)-1-Carboxy-5-[[[6-(fluoro-18F)-3-pyridinyl]carbonyl]amino]pentyl]amino]carbonyl]-L-glutamic acid
  • [18F]DCFPyl

Dcfpyl F-18

(18F)Dcfpyl

UNII-3934EF02T7

18F-DCFPyL

3934EF02T7

Progenics Pharmaceuticals, Inc.

APPROVED 5/26/2021 fda, Pylarify

For positron emission tomography imaging of prostate-specific membrane antigen-positive lesions in men with prostate cancer

For positron emission tomography (PET) of prostatespecific membrane antigen (PSMA) positive lesions in men with prostate cancer: • with suspected metastasis who are candidates for initial definitive therapy. • with suspected recurrence based on elevated serum prostate-specific antigen (PSA) level.

  • Originator Johns Hopkins University School of Medicine
  • Developer Curium Pharma; Progenics Pharmaceuticals
  • Class Amides; Carboxylic acids; Fluorinated hydrocarbons; Imaging agents; Pyridines; Radiopharmaceutical diagnostics; Radiopharmaceuticals; Small molecules; Urea compounds
  • Mechanism of ActionPositron-emission tomography enhancers
  • Orphan Drug StatusNo
  • MarketedProstate cancer
  • 28 May 2021Registered for Prostate cancer (Diagnosis) in USA (IV) – First global approval
  • 28 May 2021Adverse events data from phase III CONDOR and phase II/III OSPREY trials in prostate cancer released by Lantheus Holdings
  • 27 May 2021Lantheus Holdings intends to launch Fluorine-18 DCFPyL in USA at end of 2021

PYLARIFY contains fluorine 18 (F 18), radiolabeled prostate-specific membrane antigen inhibitor imaging agent. Chemically piflufolastat F 18 is 2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)­ amino]-pentyl}ureido)-pentanedioic acid. The molecular weight is 441.4 and the structural formula is:

str1

The chiral purity of the unlabeled piflufolastat F 18 precursor is greater than 99% (S,S). PYLARIFY is a sterile, non-pyrogenic, clear, colorless solution for intravenous injection. Each milliliter contains 37 to 2,960 MBq (1 to 80 mCi) piflufolastat F 18 with ≤0.01 µg/mCi of piflufolastat at calibration time and date, and ≤ 78.9 mg ethanol in 0.9% sodium chloride injection USP. The pH of the solution is 4.5 to 7.0. PYLARIFY has a radiochemical purity of at least 95% up to 10 hours following end of synthesis, and specific activity of at least 1000 mCi/µmol at the time of administration.

PYLARIFY contains fluorine 18 (F 18), radiolabeled prostate-specific membrane antigen inhibitor imaging agent. Chemically piflufolastat F 18 is 2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)amino]-pentyl}ureido)-pentanedioic acid. The molecular weight is 441.4 and the structural formula is:

PYLARIFY® (piflufolastat F 18) Structural Formula - Illustration

The chiral purity of the unlabeled piflufolastat F 18 precursor is greater than 99% (S,S).

PYLARIFY is a sterile, non-pyrogenic, clear, colorless solution for intravenous injection. Each milliliter contains 37 to 2,960 MBq (1 to 80 mCi) piflufolastat F 18 with ≤0.01 μg/mCi of piflufolastat at calibration time and date, and ≤ 78.9 mg ethanol in 0.9% sodium chloride injection USP. The pH of the solution is 4.5 to 7.0.

PYLARIFY has a radiochemical purity of at least 95% up to 10 hours following end of synthesis, and specific activity of at least 1000 mCi/μmol at the time of administration.

Physical Characteristics

PYLARIFY is radiolabeled with fluorine 18 (F 18), a cyclotron produced radionuclide that decays by positron emission to stable oxygen 18 with a half-life of 109.8 minutes. The principal photons useful for diagnostic imaging are the coincident pair of 511 keV gamma photons, resulting from the interaction of the emitted positron with an electron (Table 3).

Table 3: Principal Radiation Produced from Decay of Fluorine 18

 Radiation Energy (keV)Abundance (%)
Positron249.896.9
Gamma511193.5

FDA

Label (PDF)

PATENT

WO 2016030329

WO 2017072200

PAPER

Journal of Labelled Compounds and Radiopharmaceuticals (2016), 59(11), 439-450

CLIP

https://ejnmmires.springeropen.com/articles/10.1186/s13550-016-0195-6

Automated synthesis of [18F]DCFPyL via direct radiofluorination and validation in preclinical prostate cancer models

Radiosynthesis of [ 18 F]DCFPyL  

Radiosynthesis of [ 18 F]DCFPyL

figure2
figure3
figure4
figure1

Structure of 18F-labeled small-molecule PSMA inhibitors

/////////piflufolastat F 18,  injection, Orphan Drug , Prostate cancer, [18F]DCFPyL, 18F-DCFPYL, DCFPYL F-18, fda 2021, approvals 2021

C1=CC(=NC=C1C(=O)NCCCCC(C(=O)O)NC(=O)NC(CCC(=O)O)C(=O)O)F

wdt-9

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Amivantamab


(A chain)
QVQLVESGGG VVQPGRSLRL SCAASGFTFS TYGMHWVRQA PGKGLEWVAV IWDDGSYKYY
GDSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCARDG ITMVRGVMKD YFDYWGQGTL
VTVSSASTKG PSVFPLAPSS KSTSGGTAAL GCLVKDYFPE PVTVSWNSGA LTSGVHTFPA
VLQSSGLYSL SSVVTVPSSS LGTQTYICNV NHKPSNTKVD KRVEPKSCDK THTCPPCPAP
ELLGGPSVFL FPPKPKDTLM ISRTPEVTCV VVDVSHEDPE VKFNWYVDGV EVHNAKTKPR
EEQYNSTYRV VSVLTVLHQD WLNGKEYKCK VSNKALPAPI EKTISKAKGQ PREPQVYTLP
PSREEMTKNQ VSLTCLVKGF YPSDIAVEWE SNGQPENNYK TTPPVLDSDG SFLLYSKLTV
DKSRWQQGNV FSCSVMHEAL HNHYTQKSLS LSPGK
(B chain)
QVQLVQSGAE VKKPGASVKV SCETSGYTFT SYGISWVRQA PGHGLEWMGW ISAYNGYTNY
AQKLQGRVTM TTDTSTSTAY MELRSLRSDD TAVYYCARDL RGTNYFDYWG QGTLVTVSSA
STKGPSVFPL APSSKSTSGG TAALGCLVKD YFPEPVTVSW NSGALTSGVH TFPAVLQSSG
LYSLSSVVTV PSSSLGTQTY ICNVNHKPSN TKVDKRVEPK SCDKTHTCPP CPAPELLGGP
SVFLFPPKPK DTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS
TYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV YTLPPSREEM
TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL DSDGSFFLYS RLTVDKSRWQ
QGNVFSCSVM HEALHNHYTQ KSLSLSPGK
(C chain)
AIQLTQSPSS LSASVGDRVT ITCRASQDIS SALVWYQQKP GKAPKLLIYD ASSLESGVPS
RFSGSESGTD FTLTISSLQP EDFATYYCQQ FNSYPLTFGG GTKVEIKRTV AAPSVFIFPP
SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT
LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC
(D chain)
DIQMTQSPSS VSASVGDRVT ITCRASQGIS NWLAWFQHKP GKAPKLLIYA ASSLLSGVPS
RFSGSGSGTD FTLTISSLQP EDFATYYCQQ ANSFPITFGQ GTRLEIKRTV AAPSVFIFPP
SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT
LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC
(Disulfide bridge: A22-A96, A152-A208, A228-C214, A234-B228, A237-B231, A269-A329, A375-A433, B22-B96, B146-B202, B222-D214, B263-B323, B369-B427, C23-C88, C134-C194, D23-D88, D134-D194)

Amivantamab

FDA APPR 2021/5/21 Rybrevant

アミバンタマブ (遺伝子組換え)

FormulaC6472H10014N1730O2023S46
CAS2171511-58-1
Mol weight145900.1288
  • CNTO-4424
  • JNJ 61186372
  • JNJ-611
  • JNJ-61186372
EfficacyDiseaseAntineoplastic
 Non-small cell lung cancer (EGFR exon 20 insertion)
CommentMonoclonal antibody

FDA grants accelerated approval to amivantamab-vmjw for metastatic non-small cell lung cancer

https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-amivantamab-vmjw-metastatic-non-small-cell-lung-cancer

On May 21, 2021, the Food and Drug Administration granted accelerated approval to amivantamab-vmjw (Rybrevant, Janssen Biotech, Inc.), a bispecific antibody directed against epidermal growth factor (EGF) and MET receptors, for adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.

FDA also approved the Guardant360® CDx (Guardant Health, Inc.) as a companion diagnostic for amivantamab-vmjw.

Approval was based on CHRYSALIS, a multicenter, non-randomized, open label, multicohort clinical trial (NCT02609776) which included patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. Efficacy was evaluated in 81 patients with advanced NSCLC with EGFR exon 20 insertion mutations whose disease had progressed on or after platinum-based chemotherapy. Patients received amivantamab-vmjw once weekly for 4 weeks, then every 2 weeks thereafter until disease progression or unacceptable toxicity.

The main efficacy outcome measures were overall response rate (ORR) according to RECIST 1.1 as evaluated by blinded independent central review (BICR) and response duration. The ORR was 40% (95% CI: 29%, 51%) with a median response duration of 11.1 months (95% CI: 6.9, not evaluable).

The most common adverse reactions (≥ 20%) were rash, infusion-related reactions, paronychia, musculoskeletal pain, dyspnea, nausea, fatigue, edema, stomatitis, cough, constipation, and vomiting.

The recommended dose of amivantamab-vmjw is 1050 mg for patients with baseline body weight < 80 kg, and 1400 mg for those with body weight ≥ 80 kg, administered weekly for 4 weeks, then every 2 weeks thereafter until disease progression or unacceptable toxicity.

View full prescribing information for Rybrevant.

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

This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, FDA collaborated with the Brazilian Health Regulatory Agency (ANVISA) and United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA). The application reviews are ongoing at the other regulatory agencies.

This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. The FDA approved this application 2 months ahead of the FDA goal date.

This product was granted breakthrough therapy designation for this indication. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Amivantamab, sold under the brand name Rybrevant, is a monoclonal antibody medication used to treat non-small cell lung cancer.[1][2][3]

The most common side effects include rash, infusion-related reactions, skin infections around the fingernails or toenails, muscle and joint pain, shortness of breath, nausea, fatigue, swelling in the lower legs or hands or face, sores in the mouth, cough, constipation, vomiting and changes in certain blood tests.[2][3]

Amivantamab is a bispecific epidermal growth factor (EGF) receptor-directed and mesenchymal–epithelial transition (MET) receptor-directed antibody. It is the first treatment for adults with non-small cell lung cancer whose tumors have specific types of genetic mutations: epidermal growth factor receptor (EGFR) exon 20 insertion mutations.[2]

Amivantamab was approved for medical use in the United States in May 2021.[2][3][4][5]

Amivantamab, also known as JNJ-61186372, is an anti-EGFR-MET bispecific antibody, derived from Chinese hamster ovary cells, approved for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.1,9 Patients with NSCLC often develop resistance to drugs that target EGFR and MET individually, so amivantamab was developed to attack both targets, reducing the chance of resistance developing.1,2 Amivantamab was found to be more effective than the EGFR inhibitor erlotinib or the MET inhibitor crizotinib in vivo.1,3 Patients with NSCLC with exon 20 insertion mutations in EGFR do not respond to tyrosine kinase inhibitors, and were generally treated with platinum-based therapy.5

Amivantamab was granted FDA approval on 21 May 2021.9

Medical uses

Amivantamab is indicated for the treatment of adults with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.[3]

History

The U.S. Food and Drug Administration (FDA) approved amivantamab based on CHRYSALIS, a multicenter, non-randomized, open label, multicohort clinical trial (NCT02609776) which included participants with locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations.[3] Efficacy was evaluated in 81 participants with advanced NSCLC with EGFR exon 20 insertion mutations whose disease had progressed on or after platinum-based chemotherapy.[3]

The FDA collaborated on the review of amivantamab with the Brazilian Health Regulatory Agency (ANVISA) and the United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA).[3] The application reviews are ongoing at the other regulatory agencies.[3]

Society and culture

Legal status

Amivantamab was approved for medical use in the United States in May 2021.[2][3][4][5] A marketing authorization application is pending in the EU.[6][7]

Names

Amivantamab is the recommended international nonproprietary name (INN).[8]

Research

Amivantamab is being investigated in combination with lazertinib versus osimertinib; and in combination with carboplatin-pemetrexed chemotherapy compared to carboplatin-pemetrexed.[9][10]

PAPER

https://www.jbc.org/article/S0021-9258(21)00427-0/fulltext#secsectitle0085

Discovery of amivantamab (JNJ-61186372), a bispecific antibody targeting EGFR and MET

Open AccessDOI:https://doi.org/10.1016/j.jbc.2021.10064

Experimental procedures

 Preparation of BsAb panel

The generation of parental antibodies followed expression and purification protocols as described (30

,40

). The MET parental mAbs had the F405L mutation and the EGFR parental mAbs had the K409R mutation. The IgG1 b12 arm served as isotype control and null arm to preserve the BsAb architecture. The low fucose parental mAbs were generated using proprietary cell lines. The quality of the BsAb were confirmed as being monodisperse and monomeric via size exclusion chromatography and being pure via SDS-PAGE.

 Flow cytometric binding assay

Binding to cells expressing EGFR and MET (A549 [ATCC CCL-185], NCI-H1975 [ATCC, CRL-5908], and NCI-H441 [ATCC HTB-174] cells) was evaluated using flow cytometry (fluorescence-activated cell sorting [FACS]). All BsAbs and controls were diluted in FACS buffer (PBS supplemented with 1% bovine serum albumin and 0.2% sodium azide). After 1 h incubation, unbound antibodies were removed by a FACS buffer wash. The cells were then incubated with goat anti-human IgG-PE (Jackson) for FACS detection (BD FACS Canto). The mean fluorescence intensity of the cells in the live gate was plotted against antibody concentration, and the EC50 was determined by nonlinear regression fitting. Anti-EGFR zalutumumab and anti-MET 5D5 (onartuzumab) were positive controls and anti-CD20 7D8 (Genmab) was the negative control.

 MET phosphorylation assay

A549 cells were incubated with 30 μg/ml of test antibody for 15 min and tested for MET phosphorylation using rabbit anti-phospho MET (Tyr1234–1235) (Cell Signaling 3129) and total MET protein using mouse anti-human MET antibody (Cell Signaling 3127). A score of 1 to 4 was given, where 1 = no visible band, 2 = slightly visible band, 3 = phosphorylation comparable with weak agonist (MET B IgG1), and 4 = phosphorylation level similar to positive controls (MET A and MET 5D5 IgG1 mAbs).

 Proliferation assays

Test molecules were added to H1975, KP4 (Riken Cell bank, RCB1005), or NCI-H441 cells plated at 5000 or 10,000 (KP4) cells/well in 96-well plates. After 6 (KP4) or 7 (H1975 and NCI-H441) days of incubation at 37 °C and 5% CO2, the number of viable cells was determined using an AlamarBlue assay (Biosource DAL1100). A615 values were measured and plotted in a bar diagram.

 EGFR phosphorylation assay

Approximately 106 A549 or SNU-5 cells/well were grown overnight in six-well plates and incubated for 15 min with 30 μg/ml of antibody in the absence or presence of 40 ng/ml EGF. After cell lysis, Western blots determined EGFR phosphorylation status with phospho-EGFR (Tyr1068) antibody (Cell Signaling 2234) and total EGFR protein using an anti-EGFR antibody (Cell Signaling 2232).

 Expression and purification of proteins for crystallization

Human MET Sema-PSI region (residues 39–564) containing a C-terminal 8xHis tag was expressed in Tni PRO insect cells infected with recombinant baculovirus. The culture was harvested 72 h post infection, and the MET Sema-PSI protein was purified by affinity and size exclusion chromatography. Briefly, MET was captured with a Ni-NTA resin (Novagen) equilibrated in TBS, 10 mM imidazole, pH 7.4 and eluted from the column with 250 mM imidazole, TBS, pH 7.4. Fractions containing MET were identified by SDS-PAGE and loaded into a Superdex 200 column (GE Healthcare) equilibrated in 20 mM Tris, 50 mM NaCl, pH 7. The final protein concentration was determined by absorbance at 280 nm.The anti-MET Fab of amivantamab was transiently expressed in Expi293F cells. Briefly, the cells were cotransfected with separate plasmids encoding the Fab heavy and light chains at 3:1 (light:heavy chain) molar ratio following transfection kit instructions (Life Technologies). The culture was harvested 5 days post transfection, and the Fab was purified by affinity and cation exchange chromatography. Briefly, the Fab was captured with a HiTrap resin (GE Healthcare) equilibrated in PBS pH 7.2 and eluted from the column with a gradient of 30 to 300 mM imidazole in PBS pH 7.2. The eluate was buffer exchanged into 25 mM NaCl, 20 mM MES pH 6.0, bound to a Source 15S column (GE Healthcare), and eluted with a NaCl gradient in 20 mM MES pH 6.0.

 Crystallization and structure determination

The amivantamab anti-MET Fab–MET Sema-PSI complex was prepared by overnight mixing of MET and Fab at a molar ratio of 1:1.3 (excess Fab) at 4 °C, while buffer exchanging to 20 mM Hepes pH 7.0. The complex was captured with a monoS 5/50 column (GE Healthcare) equilibrated in 20 mM Hepes pH 7.0 and eluted from the column with a gradient of NaCl. The complex was concentrated to 4.8 mg/ml.Crystallization trials for the Fab–MET complex were carried out with a Mosquito LCP robot (TTP LabTech) for the setup of sitting drops on 96-well plates (Corning 3550) and a Rock Imager 54 (Formulatrix) for plate storage at 20 °C and automated imaging of drops. Small crystals were initially obtained from 2 M NH4(SO4)2, 0.1 M MES pH 6.5, and they were used as seeds in next rounds of optimization. Crystals suitable for X-ray diffraction were obtained from 2.5 M sodium formate, 5% PEG 400 Da, 0.1 M Tris pH 8.5 after multiple rounds of seeding. The crystals were soaked for a few seconds in a cryoprotectant solution containing mother liquor supplemented with 20% glycerol and then flash frozen in liquid nitrogen. X-ray diffraction data were collected with a Pilatus 6M detector on beamline 17-ID at the Advanced Photon Source (Argonne National Laboratory), and the diffraction data were processed with the program HKL2000. The crystal structure of the Fab–MET complex was solved by molecular replacement with PHASER using previously solved MET Sema-PSI (PDB code 1SHY) and anti-HER3 Fab RG7116 (PDB code 4LEO) structures as search models. The structure was refined with PHENIX, and model adjustments were performed using COOT. His tags (at C-terminal of heavy chain and PSI), Fab interchain disulfide bond, heavy chain residues 133 to 139, Sema residues 303 to 309, 407, and glycan linked to N399 are disordered and not included in the structure. The Fab was numbered sequentially and Sema-PSI numbering starts at the N terminus of the signal peptide.

Epitope and paratope residues were assigned within a 4-Å contact distance cutoff using the CCP4 program CONTACT. The epitope area was calculated with the CCP4 program AREA. The buried surface area of binding residues was calculated with the program MOE (47

). Structural overlays of equivalent Cα atoms in the Sema domain (residues 40–515; PDB codes 1SHY, 4K3J, 2UZX, and 2UZY) were performed with COOT. Molecular graphics were generated with PyMol (PyMOL Molecular Graphics System, Version 1.4.1, Schrödinger, LLC) and MOE. The atomic coordinates and structure factors for the amivantamab anti-MET Fab–MET Sema-PSI complex were deposited in the RCSB PDB (accession code 6WVZ).

 HCC827-HGF xenograft model

Female SCID Beige mice CB17.B6-Prkdcscid Lystbg/Crl (Charles River) bearing established subcutaneous HCC827-HGF tumors were randomized 13 days post inoculation (day 1). Individual tumor volumes ranged from 144 to 221 mm3; mean tumor volume ranged from 180 to 184 mm3. PBS and amivantamab (10 mg/kg) were dosed i.p. biweekly for 3 weeks. Crizotinib (30 mg/kg), erlotinib (25 mg/kg), crizotinib (30 mg/kg) and erlotinib (25 mg/kg), and vehicle controls (0.5% carboxymethyl cellulose in sterile water and 1% carboxymethyl cellulose in 0.1% Tween 80) were dosed daily p.o. for 3 weeks. Subcutaneous tumors were measured twice weekly as the mean tumor volume (mm3 ± standard error of the mean [SEM]). To calculate the percent tumor growth inhibition (%TGI) for group A versus group B, the tumor volumes were log transformed, where A = treated and B = control. The difference between these transformed values was taken at day 1 versus the designated day. Means were taken and converted by anti-log to numerical scale. Percentage TGIs were then calculated as (1 − A/B) × 100%. In vivo experiment was reviewed and approved by the Charles River Laboratories Institutional Animal Care and Use Committee and was done in accordance with the Guide for Care and Use of Laboratory Animals.

References

  1. Jump up to:a b “Rybrevant- amivantamab injection”DailyMed. Janssen Pharmaceutical Companies. Retrieved 25 May 2021.
  2. Jump up to:a b c d e f “FDA Approves First Targeted Therapy for Subset of Non-Small Cell Lung Cancer”U.S. Food and Drug Administration (FDA) (Press release). 21 May 2021. Retrieved 21 May 2021.  This article incorporates text from this source, which is in the public domain.
  3. Jump up to:a b c d e f g h i j “FDA grants accelerated approval to amivantamab-vmjw for mNSCLC”U.S. Food and Drug Administration (FDA). 21 May 2021. Retrieved 21 May 2021.  This article incorporates text from this source, which is in the public domain.
  4. Jump up to:a b “Rybrevant (amivantamab-vmjw) Receives FDA Approval as the First Targeted Treatment for Patients with Non-Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations” (Press release). Janssen Pharmaceutical Companies. 21 May 2021. Retrieved 21 May 2021 – via PR Newswire.
  5. Jump up to:a b “Genmab Announces that Janssen has been Granted U.S. FDA” (Press release). Genmab A/S. 21 May 2021. Retrieved 21 May 2021 – via GlobeNewswire.
  6. ^ “Amivantamab”SPS – Specialist Pharmacy Service. 25 February 2021. Retrieved 23 May 2021.
  7. ^ “Janssen Submits European Marketing Authorisation Application for Amivantamab for the Treatment of Patients with Metastatic Non-Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations” (Press release). Janssen Pharmaceutical Companies. 28 December 2020. Retrieved 23 May 2021 – via Business Wire.
  8. ^ World Health Organization (2020). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 83” (PDF). WHO Drug Information34 (1).
  9. ^ Kaplon H, Reichert JM (2021). “Antibodies to watch in 2021”mAbs13 (1): 1860476. doi:10.1080/19420862.2020.1860476PMC 7833761PMID 33459118.
  10. ^ “Updated Amivantamab and Lazertinib Combination Data Demonstrate Durable Responses and Clinical Activity for Osimertinib-Relapsed Patients with EGFR-Mutated Non-Small Cell Lung Cancer” (Press release). Janssen Pharmaceutical Companies. 20 May 2021. Retrieved 23 May 2021 – via Business Wire.

Further reading

External links

  • “Amivantamab”Drug Information Portal. U.S. National Library of Medicine.
  • Clinical trial number NCT02609776 for “Study of Amivantamab, a Human Bispecific EGFR and cMet Antibody, in Participants With Advanced Non-Small Cell Lung Cancer (CHRYSALIS)” at ClinicalTrials.gov
Monoclonal antibody
TypeWhole antibody
SourceHuman
TargetEpidermal growth factor receptor (EGFR) and Mesenchymal–epithelial transition (MET)
Clinical data
Trade namesRybrevant
Other namesJNJ-61186372, amivantamab-vmjw
License dataUS DailyMedAmivantamab
Routes of
administration
Intravenous infusion
Drug classAntineoplastic
ATC codeNone
Legal status
Legal statusUS: ℞-only [1][2][3]
Identifiers
CAS Number2171511-58-1
DrugBankDB16695
UNII0JSR7Z0NB6
KEGGD11894
Chemical and physical data
FormulaC6472H10014N1730O2023S46
Molar mass145902.15 g·mol−1
NAMEDOSAGESTRENGTHROUTELABELLERMARKETING STARTMARKETING END  
RybrevantInjection350 mg/1IntravenousJanssen Biotech, Inc.2021-05-21Not applicableUS flag 

/////////Amivantamab, FDA 2021, APPROVALS 2021, PEPTIDE, Rybrevant, アミバンタマブ (遺伝子組換え), CNTO-4424, JNJ 61186372, JNJ-611, JNJ-61186372, breakthrough therapy designation, Janssen Biotech

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Pegcetacoplan


Sequence:

1ICVWQDWGAH RCTXK

Sequence:

1ICVWQDWGAH RCTXK

Sequence Modifications

TypeLocationDescription
terminal mod.Lys-15C-terminal amide
terminal mod.Lys-15′C-terminal amide
bridgeCys-2 – Cys-12disulfide bridge, dimer
bridgeLys-15 – Lys-15′covalent bridge, dimer
bridgeCys-2′ – Cys-12′disulfide bridge, dimer
uncommonOaa-14
uncommonOaa-14′

Pegcetacoplan

ペグセタコプラン;

FDA APPROVED Empaveli, 2021/5/14

Protein Sequence

Sequence Length: 30, 15, 15multichain; modifiedPoly(oxy-1,2-ethanediyl), α-hydro-ω-hydroxy-, 15,15′-diester with N-acetyl-L-isoleucyl-L-cysteinyl-L-valyl-1-methyl-L-tryptophyl-L-glutaminyl-L-α-aspartyl-L-tryptophylglycyl-L-alanyl-L-histidyl-L-arginyl-L-cysteinyl-L-threonyl-2-[2-(2-aminoethoxy)ethoxy]acetyl-N6-carboxy-L-lysinamide cyclic (2→12)-(disulfide)Polymer

Poly(oxy-1,2-ethanediyl), alpha-hydro-omega-hydroxy-, 15,15′-diester with N-acetyl-Lisoleucyl-L-cysteinyl-L-valyl-1-methyl-L-tryptophyl-L-glutaminyl-L-alpha-aspartyl-L-tryptophylglycyl-L-alanyl-L-histidyl-L-arginyl-L-cysteinyl-L-threonyl-2-(2-(2-aminoethoxy)ethoxy)acetyl-N6-carboxy-L-lysinamide cyclic (2�-&gt;12)-(disulfide)

O,O’-bis((S2,S12-cyclo(N-acetyl-L-isoleucyl-L-cysteinyl-L-valyl-1-methyl-Ltryptophyl-L-glutaminyl-L-alpha-aspartyl-L-tryptophylglycyl-L-alanyl-L-histidyl-L-arginyl-L-cysteinyl-L-threonyl-2-(2-(2-aminoethoxy)ethoxy)acetyl-L-lysinamide))-N6.15-carbonyl)polyethylene glycol(n = 800-1100)

  • APL-2
  • WHO 10743
FormulaC170H248N50O47S4. (C2H4O)n3872.40 g·mol−1
EfficacyDiseaseComplement inhibitorParoxysmal nocturnal hemoglobinuria
  CAS2019171-69-6
CommentTreatment of paroxysmal nocturnal hemoglobinuria (PNH), complement-mediated nephropathies, and age-related macular degeneration (AMD)
  • OriginatorApellis Pharmaceuticals
  • ClassAnti-inflammatories; Anti-ischaemics; Antianaemics; Cyclic peptides; Eye disorder therapies; Polyethylene glycols; Urologics
  • Mechanism of ActionComplement C3 inhibitors
  • Orphan Drug StatusYes – Paroxysmal nocturnal haemoglobinuria; Autoimmune haemolytic anaemia; Glomerulonephritis
  • RegisteredParoxysmal nocturnal haemoglobinuria
  • Phase IIIAge-related macular degeneration
  • Phase IIAmyotrophic lateral sclerosis; Autoimmune haemolytic anaemia; Glomerulonephritis; IgA nephropathy; Lupus nephritis; Membranous glomerulonephritis
  • Phase I/IIWet age-related macular degeneration
  • DiscontinuedIschaemia
  • 02 Jun 2021Apellis Pharmaceuticals plans a phase III trial for Glomerulonephritis in the second half of 2021
  • 25 May 2021Top-line efficacy and safety results from the phase III PRINCE trial for Paroxysmal nocturnal haemoglobinuria released by Apellis Pharmaceuticals
  • 18 May 2021Registered for Paroxysmal nocturnal haemoglobinuria in USA (SC) – First global approval

Pegcetacoplan, sold under the brand name Empaveli, is a medication used to treat paroxysmal nocturnal hemoglobinuria (PNH).[1][2]

The most common side effects include injection-site reactions, infections, diarrheaabdominal pain, respiratory tract infection, viral infection, and fatigue.[2]

Paroxysmal nocturnal hemoglobinuria is characterized by red blood cell destruction, anemia (red blood cells unable to carry enough oxygen to tissues), blood clots, and impaired bone marrow function (not making enough blood cells).[1]

Pegcetacoplan is the first treatment for paroxysmal nocturnal hemoglobinuria that binds to complement protein C3.[1] Pegcetacoplan was approved for medical use in the United States in May 2021.[1][3]

Pegcetacoplan is a complement inhibitor indicated in the treatment of paroxysmal nocturnal hemoglobinuria (PNH).5,7 Prior to its FDA approval, patients with PNH were typically treated with the C5 inhibiting monoclonal antibody eculizumab.5 Patients given eculizumab experienced less hemolysis caused by the membrane attack complex, but were still somewhat susceptible to hemolysis caused by C3b opsonization.5,6 Pegcetacoplan was developed out of a need for an inhibitor of complement mediated hemolysis further upstream of C5.5,6 Pegcetacoplan is a pegylated C3 inhibitor that can disrupt the processes leading to both forms of hemolysis that threaten patients with PNH.5

Pegcetacoplan was granted FDA approval on 14 May 2021.7

Medical uses

Pegcetacoplan is indicated to treat adults with paroxysmal nocturnal hemoglobinuria (PNH).[1][2]

EMPAVELI contains pegcetacoplan, a complement inhibitor. Pegcetacoplan is a symmetrical molecule comprised of two identical pentadecapeptides covalently bound to the ends of a linear 40-kiloDalton (kDa) PEG molecule. The peptide portions of pegcetacoplan contain 1-methyl-L-tryptophan (Trp(Me)) in position 4 and amino(ethoxyethoxy)acetic acid (AEEA) in position 14.

The molecular weight of pegcetacoplan is approximately 43.5 kDa. The molecular formula is C1970H3848N50O947S4. The structure of pegcetacoplan is shown below.

EMPAVELI™ (pegcetacoplan) Structural Formula - Illustration

EMPAVELI injection is a sterile, clear, colorless to slightly yellowish aqueous solution for subcutaneous use and is supplied in a 20-mL single-dose vial. Each 1 mL of solution contains 54 mg of pegcetacoplan, 41 mg of sorbitol, 0.384 mg of glacial acetic acid, 0.490 mg of sodium acetate trihydrate, and Water for Injection USP. EMPAVELI may also contain sodium hydroxide and/or additional glacial acetic acid for adjustment to a target pH of 5.0.

FDA approves new treatment for adults with serious rare blood disease..

https://www.fda.gov/drugs/drug-safety-and-availability/fda-approves-new-treatment-adults-serious-rare-blood-disease

FDA has approved Empaveli (pegcetacoplan) injection to treat adults with paroxysmal nocturnal hemoglobinuria (PNH), a rare, life-threatening blood disease. Empaveli is the first PNH treatment that binds to compliment protein C3.

PNH is characterized by red blood cell destruction, anemia (red blood cells unable to carry enough oxygen to tissues), blood clots, and impaired bone marrow function (not making enough blood cells). The disease affects 1-1.5 people per million. Individuals are typically diagnosed around ages 35 to 40. PNH can be serious, with median survival of 10 years after diagnosis. However, some patients live for decades with only minor symptoms.

PNH is caused by gene mutations that affect red blood cells. Red blood cells in people with these mutations are defective and can be destroyed by the immune system, which causes anemia.

The effectiveness of Empaveli was evaluated in a study enrolling 80 patients with PNH and anemia who had been taking eculizumab, a treatment previously approved for PNH. Patients first completed a four-week period during which they received Empaveli 1,080 mg twice weekly in addition to eculizumab at their previous dose. After the first four weeks, patients were randomly assigned to receive either Empaveli or their current dose of eculizumab for 16 weeks.

After 16 weeks, the severity of anemia was compared in the two treatment groups on the basis of hemoglobin concentration (a laboratory measure of anemia). In both treatment groups, the average hemoglobin was 8.7 g/dL at baseline, indicating severe anemia. (Normal hemoglobin values in adult men are 14 g/dL or above; normal values in adult women are 12 g/dL or above.) During the 16 weeks of treatment, patients in the Empaveli group had an average increase in their hemoglobin of 2.4 g/dL. Meanwhile, patients in the eculizumab group had an average decrease in their hemoglobin of 1.5 g/dL.

Empaveli is available only through a restricted program under a risk evaluation and mitigation strategy. Meningococcal (a type of bacteria) infections can occur in patients taking Empaveli and can become life-threatening or fatal if not treated early. Empaveli may also predispose individuals to serious infections, especially infections caused by encapsulated bacteria. Patients should be monitored for infusion-related reactions. Empaveli can interfere with certain laboratory tests. The most common side effects are injection site reactions, infections, diarrhea, abdominal pain, respiratory tract infection, viral infection, and fatigue.

Empaveli received priority reviewfast track and orphan drug designations for this indication.

FDA granted the approval of Empaveli to Apellis Pharmaceuticals.

Adverse effects

Meningococcal (a type of bacteria) infections can occur in people taking pegcetacoplan and can become life-threatening or fatal if not treated early.[1] Pegcetacoplan may also predispose individuals to serious infections, especially infections caused by encapsulated bacteria.[1]

History

The effectiveness of pegcetacoplan was evaluated in a study enrolling 80 participants with paroxysmal nocturnal hemoglobinuria and anemia who had been taking eculizumab, a treatment previously approved for paroxysmal nocturnal hemoglobinuria.[1]

References

  1. Jump up to:a b c d e f g h i “FDA approves new treatment for adults with serious rare blood disease”U.S. Food and Drug Administration (FDA). 14 May 2021. Retrieved 14 May 2021.  This article incorporates text from this source, which is in the public domain.
  2. Jump up to:a b c d https://pi.apellis.com/files/PI_Empaveli.pdf
  3. ^ “Apellis Announces U.S. Food and Drug Administration (FDA) Approval of Empaveli (pegcetacoplan) for Adults with Paroxysmal Nocturnal Hemoglobinuria (PNH)” (Press release). Apellis Pharmaceuticals. 14 May 2021. Retrieved 14 May 2021 – via GlobeNewswire.

External links

  • “Pegcetacoplan”Drug Information Portal. U.S. National Library of Medicine.
  • Clinical trial number NCT03500549 for “Study to Evaluate the Efficacy and Safety of APL-2 in Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH)” at ClinicalTrials.gov
Clinical data
Trade namesEmpaveli
Other namesAPL-2
License dataUS DailyMedPegcetacoplan
Routes of
administration
Subcutaneous infusion
Drug classComplement inhibitor
ATC codeNone
Legal status
Legal statusUS: ℞-only [1][2]
Identifiers
CAS Number2019171-69-6
UNIITO3JYR3BOU
KEGGD11613
ChEMBLChEMBL4298211
Chemical and physical data
FormulaC170H248N50O47S4
Molar mass3872.40 g·mol−1

/////////Pegcetacoplan, ペグセタコプラン , FDA 2021, APPROVALS 2021, APL-2, WHO 10743, Apellis Pharmaceuticals, Empaveli, priority reviewfast track,  orphan drug

https://www.sec.gov/Archives/edgar/data/1492422/000156459020007350/apls-10k_20191231.htm

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