The discovery of BMS-737 as a potent, CYP17 lyase-selective inhibitor for the treatment of castration-resistant prostate cancer

被引：7

作者：

Darne, Chetan Padmakar ^{[1
]}

Velaparthi, Upender ^{[1
]}

Saulnier, Mark ^{[1
]}

Frennesson, David ^{[1
]}

Liu, Peiying ^{[1
]}

Huang, Audris ^{[1
]}

Tokarski, John ^{[1
]}

Fura, Aberra ^{[1
]}

Spires, Thomas ^{[1
]}

Newitt, John ^{[1
]}

Spires, Vanessa M. ^{[1
]}

Obermeier, Mary T. ^{[1
]}

Elzinga, Paul A. ^{[1
]}

Gottardis, Marco M. ^{[1
]}

Jayaraman, Lata ^{[1
]}

Vite, Gregory D. ^{[1
]}

Balog, Aaron ^{[1
]}

机构：

[1] Bristol Myers Squibb Co, POB 4000, Princeton, NJ 08543 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2022年 / 75卷

关键词：

Castration-resistant prostate cancer (CRPC); Lyase; Hydroxylase; Glucocorticoids; Mineralocorticoids; abiraterone acetate (AA); Aza-indazole; ORTERONEL TAK-700; 17,20-LYASE INHIBITOR; CYTOCHROME-P450; 17A1; ABIRATERONE ACETATE; ANDROGEN RECEPTOR; PLUS PREDNISONE; PHASE-I; ANTIANDROGEN; REPLACEMENT; MULTICENTER;

D O I：

10.1016/j.bmcl.2022.128951

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We report herein, the discovery of BMS-737 (compound 33) as a potent, non-steroidal, reversible small molecule inhibitor demonstrating 11-fold selectivity for CYP17 lyase over CYP17 hydroxylase, as well as a clean xenobiotic CYP profile for the treatment of castration-resistant prostate cancer (CRPC). Extensive SAR studies on the initial lead 1 at three different regions of the molecule resulted in the identification of BMS-737, which demonstrated a robust 83% lowering of testosterone without any significant perturbation of the mineralocorticoid and gluco-corticoid levels in cynomologous monkeys in a 1-day PK/PD study.

引用

页数：10

共 49 条

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