title: Discovery of the Selective CYP17A1 Lyase Inhibitor BMS-351 for the Treatment of Prostate Cancer.
abstract: Efforts to identify a potent, reversible, nonsteroidal CYP17A1 lyase inhibitor with good selectivity over CYP17A1 hydroxylase and CYPs 11B1 and 21A2 for the treatment of castration-resistant prostate cancer (CRPC) culminated in the discovery of BMS-351 (compound 18), a pyridyl biaryl benzimidazole with an excellent in vivo profile. Biological evaluation of BMS-351 at a dose of 1.5 mg in castrated cynomolgus monkeys revealed a remarkable reduction in testosterone levels with minimal glucocorticoid and mineralcorticoid perturbation. Based on a favorable profile, BMS-351 was selected as a candidate for further preclinical evaluation.
authors.affiliation: Bristol-Myers Squibb Research and Development , Princeton, New Jersey 08543-4000, United States.
authors.forename: Audris
authors.initials: A
authors.lastname: Huang
authors.affiliation: Bristol-Myers Squibb Research and Development , Princeton, New Jersey 08543-4000, United States.
authors.forename: Lata
authors.initials: L
authors.lastname: Jayaraman
authors.affiliation: Bristol-Myers Squibb Research and Development , Princeton, New Jersey 08543-4000, United States.
authors.forename: Aberra
authors.initials: A
authors.lastname: Fura
authors.affiliation: Bristol-Myers Squibb Research and Development , Princeton, New Jersey 08543-4000, United States.
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Vite
authors.affiliation: Bristol-Myers Squibb Research and Development , Princeton, New Jersey 08543-4000, United States.
authors.forename: George L
authors.initials: GL
authors.lastname: Trainor
authors.affiliation: Bristol-Myers Squibb Research and Development , Princeton, New Jersey 08543-4000, United States.
authors.forename: Marco M
authors.initials: MM
authors.lastname: Gottardis
authors.affiliation: Bristol-Myers Squibb Research and Development , Princeton, New Jersey 08543-4000, United States.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Spires
authors.affiliation: Bristol-Myers Squibb Research and Development , Princeton, New Jersey 08543-4000, United States.
authors.forename: Vanessa M
authors.initials: VM
authors.lastname: Spires
authors.affiliation: Bristol-Myers Squibb Research and Development , Princeton, New Jersey 08543-4000, United States.
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Rizzo
authors.affiliation: Bristol-Myers Squibb Research and Development , Princeton, New Jersey 08543-4000, United States.
authors.forename: Mary T
authors.initials: MT
authors.lastname: Obermeier
authors.affiliation: Bristol-Myers Squibb Research and Development , Princeton, New Jersey 08543-4000, United States.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Elzinga
authors.affiliation: Bristol-Myers Squibb Research and Development , Princeton, New Jersey 08543-4000, United States.
authors.forename: Gordon
authors.initials: G
authors.lastname: Todderud
authors.affiliation: Bristol-Myers Squibb Research and Development , Princeton, New Jersey 08543-4000, United States.
authors.forename: Yi
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Bristol-Myers Squibb Research and Development , Princeton, New Jersey 08543-4000, United States.
authors.forename: John A
authors.initials: JA
authors.lastname: Newitt
authors.affiliation: Bristol-Myers Squibb Research and Development , Princeton, New Jersey 08543-4000, United States.
authors.forename: Sophie M
authors.initials: SM
authors.lastname: Beyer
authors.affiliation: Bristol-Myers Squibb Research and Development , Princeton, New Jersey 08543-4000, United States.
authors.forename: Yongxin
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Bristol-Myers Squibb Research and Development , Princeton, New Jersey 08543-4000, United States.
authors.forename: Bethanne M
authors.initials: BM
authors.lastname: Warrack
authors.affiliation: Bristol-Myers Squibb Research and Development , Princeton, New Jersey 08543-4000, United States.
authors.forename: Angela K
authors.initials: AK
authors.lastname: Goodenough
authors.affiliation: Bristol-Myers Squibb Research and Development , Princeton, New Jersey 08543-4000, United States.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Tebben
authors.affiliation: Bristol-Myers Squibb Research and Development , Princeton, New Jersey 08543-4000, United States.
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Doweyko
authors.affiliation: Bristol-Myers Squibb Research and Development , Princeton, New Jersey 08543-4000, United States.
authors.forename: David L
authors.initials: DL
authors.lastname: Gold
authors.affiliation: Bristol-Myers Squibb Research and Development , Princeton, New Jersey 08543-4000, United States.
authors.forename: Aaron
authors.initials: A
authors.lastname: Balog
keywords: CYP11B1; CYP17A1; CYP21A2; Prostate cancer; benzimidazoles; cortisol; lyase
references.citation: J Steroid Biochem Mol Biol. 2012 Apr;129(3-5):115-28
references.pmid: 22249003
references.citation: Ann Pharmacother. 2012 Nov;46(11):1518-28
references.pmid: 23136351
references.citation: Mol Cell Endocrinol. 2012 Sep 5;360(1-2):68-75
references.pmid: 21986558
references.citation: Rev Urol. 2009 Spring;11(2):52-60
references.pmid: 19680526
references.citation: J Am Chem Soc. 2001 Aug 8;123(31):7727-9
references.pmid: 11481007
references.citation: CA Cancer J Clin. 1972 Jul-Aug;22(4):232-40
references.pmid: 4625049
references.citation: J Org Chem. 2002 Jul 26;67(15):5394-7
references.pmid: 12126436
references.citation: Curr Oncol Rep. 2013 Apr;15(2):105-12
references.pmid: 23371447
references.citation: Cancer Biol Ther. 2012 Sep;13(11):1001-8
references.pmid: 22825325
references.citation: J Org Chem. 2004 Aug 20;69(17):5578-87
references.pmid: 15307726
references.citation: J Mol Biol. 2008 Jun 27;380(1):95-106
references.pmid: 18511070
references.citation: Ann Surg. 1942 Jun;115(6):1192-200
references.pmid: 17858048
references.citation: Semin Reprod Med. 2004 Nov;22(4):299-309
references.pmid: 15635498
references.citation: Nature. 2012 Jan 22;482(7383):116-9
references.pmid: 22266943
references.citation: Bioorg Med Chem. 2011 Nov 1;19(21):6383-99
references.pmid: 21978946
references.citation: Clin Cancer Res. 2012 Apr 1;18(7):1848-54
references.pmid: 22451619