BMS-641988
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[edit | edit source]
- ↑ 1.0 1.1 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 Res., Vol. 69(Issue: 16), pp. 6522–30, 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, Curr. Med. Chem., Vol. 23(Issue: 8), pp. 792–815, DOI: 10.2174/0929867323666160210125642, PMID: 26861003, PMC: 5412001, Full text,
- ↑ 4.0 4.1 4.2 , Novel, potent anti-androgens of therapeutic potential: recent advances and promising developments, Future Med Chem, Vol. 2(Issue: 4), pp. 667–80, 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, Clin. Cancer Res., Vol. 17(Issue: 4), pp. 880–7, DOI: 10.1158/1078-0432.CCR-10-2955, PMID: 21131556, PMC: 3070382,
- ↑ 6.0 6.1 , Accounts in Drug Discovery: Case Studies in Medicinal Chemistry. online version, Royal Society of Chemistry, ISBN 978-1-84973-198-0, Pages: 120–,
External links[edit | edit source]
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