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

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• 作者：Audris Huang ; Lata Jayaraman ; Aberra Fura ; Gregory D. Vite ; George L. Trainor ; Marco M. Gottardis ; Thomas E. Spires ; Vanessa M. Spires ; Cheryl A. Rizzo ; Mary T. Obermeier ; Paul A. Elzinga ; Gordon Todderud ; Yi Fan ; John A. Newitt ; Sophie M. Beyer ; Yongxin Zhu ; Bethanne M. Warrack ; Angela K. Goodenough ; Andrew J. Tebben ; Arthur M. Doweyko ; David L. Gold ; Aaron Balog
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：January 14, 2016
• 年：2016
• 卷：7
• 期：1
• 页码：40-45
• 全文大小：424K
• ISSN：1948-5875

文摘

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.