Bristol-Myers Squibb Company, P.O. Box 4000, Princeton, NJ 08543, United States.
Bristol-Myers Squibb Company, P.O. Box 4000, Princeton, NJ 08543, United States.
Bioorg Med Chem Lett. 2022 Nov 1;75:128951. doi: 10.1016/j.bmcl.2022.128951. Epub 2022 Aug 27.
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 glucocorticoid levels in cynomologous monkeys in a 1-day PK/PD study.
我们在此报告，发现 BMS-737（化合物 33）是一种有效的、非甾体、可逆的小分子抑制剂，对 CYP17 裂解酶的选择性比 CYP17 羟化酶高 11 倍，同时对异源生物 CYP 具有清晰的特征，可用于治疗去势抵抗性前列腺癌（CRPC）。在分子的三个不同区域对初始先导物 1 进行广泛的 SAR 研究，导致发现了 BMS-737，在 1 天的 PK/PD 研究中，它在恒河猴中使睾酮降低了 83%，而对盐皮质激素和糖皮质激素水平没有任何显著影响。
