Chemistry:BMS-641988
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| Routes of administration | By mouth |
| Drug class | Nonsteroidal antiandrogen |
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| Formula | C20H20F3N3O5S |
| Molar mass | 471.45 g·mol−1 |
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BMS-641988 is a nonsteroidal antiandrogen which was developed by Bristol-Myers Squibb for the treatment of prostate cancer but was never marketed.[1][2][3] It acts as a potent competitive antagonist of the androgen receptor (AR) (Ki = 10 nM; IC50 = 56 nM).[3] The drug was found to have 20-fold higher affinity for the AR than bicalutamide in MDA-MB-453 cells, and showed 3- to 7-fold the antiandrogenic activity of bicalutamide in vitro.[4] It may have some weak partial agonist activity at the androgen receptor.[4] BMS-641988 is transformed by CYP3A4 into BMS-570511, and this metabolite is then reduced to BMS-501949 by cytosolic reductases.[5][4] All three compounds show similar antiandrogenic activity.[5] In addition to its antiandrogenic activity, BMS-641988 shows activity as a negative allosteric modulator of the GABAA receptor, and can produce seizures in animals at sufficiently high doses.[6] It also shows some drug-induced QT prolongation.[6] BMS-641988 reached phase I clinical trials prior to the discontinuation of its development.[1] The clinical development of BMS-641988 was terminated due to the occurrence of a seizure in a patient during a phase I study.[5]
References
- ↑ 1.0 1.1 "BMS 641988". AdisInsight. Springer Nature Switzerland AG. https://adisinsight.springer.com/drugs/800026026.
- ↑ "Discovery of BMS-641988, a novel and potent inhibitor of androgen receptor signaling for the treatment of prostate cancer". Cancer Research 69 (16): 6522–6530. August 2009. doi:10.1158/0008-5472.CAN-09-1111. PMID 19654297.
- ↑ 3.0 3.1 "Recent Advances in Drug Design and Drug Discovery for Androgen- Dependent Diseases". Current Medicinal Chemistry 23 (8): 792–815. 2016. doi:10.2174/0929867323666160210125642. PMID 26861003.
- ↑ 4.0 4.1 4.2 "Novel, potent anti-androgens of therapeutic potential: recent advances and promising developments". Future Medicinal Chemistry 2 (4): 667–680. April 2010. doi:10.4155/fmc.10.14. PMID 21426013.
- ↑ 5.0 5.1 5.2 "Phase I dose-escalation study of the novel antiandrogen BMS-641988 in patients with castration-resistant prostate cancer". Clinical Cancer Research 17 (4): 880–887. February 2011. doi:10.1158/1078-0432.CCR-10-2955. PMID 21131556.
- ↑ 6.0 6.1 "Novel Androgen Receptor Antagonists for the Treatment of Prostate Cancer". Accounts in Drug Discovery: Case Studies in Medicinal Chemistry. Royal Society of Chemistry. 30 September 2010. pp. 120–. ISBN 978-1-84973-198-0. https://books.google.com/books?id=jHIoDwAAQBAJ&pg=PA120.
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