Discovery of the Selective CYP17A1 Lyase Inhibitor BMS-351 for the Treatment of Prostate Cancer

• Published in: ACS medicinal chemistry letters Vol. 7; no. 1; pp. 40 - 45
• Main Authors: Huang, Audris, Jayaraman, Lata, Fura, Aberra, Vite, Gregory D, Trainor, George L, Gottardis, Marco M, Spires, Thomas E, Spires, Vanessa M, Rizzo, Cheryl A, Obermeier, Mary T, Elzinga, Paul A, Todderud, Gordon, Fan, Yi, Newitt, John A, Beyer, Sophie M, Zhu, Yongxin, Warrack, Bethanne M, Goodenough, Angela K, Tebben, Andrew J, Doweyko, Arthur M, Gold, David L, Balog, Aaron
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 14.01.2016; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; Letter; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; cortisol; CYP21A2; CYP11B1; benzimidazoles; lyase; Prostate cancer; CYP17A1; 17,20-LYASE INHIBITOR; CASTRATION-RESISTANT; N-ARYLATION; ORTERONEL TAK-700; ABIRATERONE
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/acsmedchemlett.5b00310

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.