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

被引：7

作者：

Huang, Audris ^{[1
]}

Jayaraman, Lata ^{[1
]}

Fura, Aberra ^{[1
]}

Vite, Gregory D. ^{[1
]}

Trainor, George L. ^{[1
]}

Gottardis, Marco M. ^{[1
]}

Spires, Thomas E. ^{[1
]}

Spires, Vanessa M. ^{[1
]}

Rizzo, Cheryl A. ^{[1
]}

Obermeier, Mary T. ^{[1
]}

Elzinga, Paul A. ^{[1
]}

Todderud, Gordon ^{[1
]}

Fan, Yi ^{[1
]}

Newitt, John A. ^{[1
]}

Beyer, Sophie M. ^{[1
]}

Zhu, Yongxin ^{[1
]}

Warrack, Bethanne M. ^{[1
]}

Goodenough, Angela K. ^{[1
]}

Tebben, Andrew J. ^{[1
]}

Doweyko, Arthur M. ^{[1
]}

Gold, David L. ^{[1
]}

Balog, Aaron ^{[1
]}

机构：

[1] Bristol Myers Squibb Res & Dev, Princeton, NJ 08543 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2016年 / 7卷 / 01期

关键词：

Prostate cancer; CYP17A1; benzimidazoles; lyase; CYP11B1; CYP21A2; cortisol; CASTRATION-RESISTANT; 17,20-LYASE INHIBITOR; ORTERONEL TAK-700; N-ARYLATION; ABIRATERONE;

D O I：

10.1021/acsmedchemlett.5b00310

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Efforts to identify a potent, reversible, non steroidal 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.

引用

页码：40 / 45

页数：6

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