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BMS-641988

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BMS-641988
Clinical data
Routes of
administration
By mouth
Drug classNonsteroidal antiandrogen
Identifiers
  • 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
PubChem CID
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC20H20F3N3O5S
Molar mass471.45 g·mol−1
3D model (JSmol)
  • 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=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

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; 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 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]
  1. ^ a b "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. ^ a b 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. ^ a b c 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. ^ a b c 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. ^ a b 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.