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) (K_i = 10 nM; IC₅₀Tooltip half-maximal inhibitory concentration = 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 GABA_A 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]

BMS-641988

Clinical data
Routes of administration	By mouth
Drug class	Nonsteroidal antiandrogen
Identifiers
IUPAC name N-[(3aR,4R,5R,7R,7aS)-2-[4-cyano-3-(trifluoromethyl)phenyl]-4,7-dimethyl-1,3-dioxo-3a,5,6,7a-tetrahydro-octahydro-1H-4,7-epoxyisoindol-5-yl]ethanesulfonamide
CAS Number	1093276-09-5 573738-99-5
PubChem CID	24768935
UNII	W17M53Y8IM
ChEBI	CHEBI:95017
ChEMBL	ChEMBL3932464
CompTox Dashboard (EPA)	DTXSID70205969
Chemical and physical data
Formula	C20H20F3N3O5S
Molar mass	471.45 g·mol−1
3D model (JSmol)	Interactive image
SMILES CCS(=O)(=O)N[C@@H]1C[C@@]2([C@@H]3[C@H]([C@]1(O2)C)C(=O)N(C3=O)C4=CC(=C(C=C4)C#N)C(F)(F)F)C
InChI InChI=1S/C20H20F3N3O5S/c1-4-32(29,30)25-13-8-18(2)14-15(19(13,3)31-18)17(28)26(16(14)27)11-6-5-10(9-24)12(7-11)20(21,22)23/h5-7,13-15,25H,4,8H2,1-3H3/t13-,14-,15+,18-,19+/m1/s1 Key:HYNANJUKEMCYEQ-HIGHGGLBSA-N

References

1. "BMS 641988". AdisInsight. Springer Nature Switzerland AG.
2. Attar RM, Jure-Kunkel M, Balog A, Cvijic ME, Dell-John J, Rizzo CA, et al. (August 2009). "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. doi:10.1158/0008-5472.CAN-09-1111. PMID 19654297.
3. Cabeza M, Sánchez-Márquez A, Garrido M, Silva A, Bratoeff E (2016). "Recent Advances in Drug Design and Drug Discovery for Androgen- Dependent Diseases". Current Medicinal Chemistry. 23 (8): 792–815. doi:10.2174/0929867323666160210125642. PMC 5412001. PMID 26861003.
4. Vasaitis TS, Njar VC (April 2010). "Novel, potent anti-androgens of therapeutic potential: recent advances and promising developments". Future Medicinal Chemistry. 2 (4): 667–680. doi:10.4155/fmc.10.14. PMID 21426013. S2CID 36343891.
5. Rathkopf D, Liu G, Carducci MA, Eisenberger MA, Anand A, Morris MJ, et al. (February 2011). "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. doi:10.1158/1078-0432.CCR-10-2955. PMC 3070382. PMID 21131556.
6. Gavai AV, Foster WR, Balog A, Vite GD (30 September 2010). "Novel Androgen Receptor Antagonists for the Treatment of Prostate Cancer". In Barrish J, Carter P, Cheng P, Zahler R (eds.). Accounts in Drug Discovery: Case Studies in Medicinal Chemistry. Royal Society of Chemistry. pp. 120–. ISBN 978-1-84973-198-0.