Discovery of the Selective CYP17A1 Lyase Inhibitor BMS-351 for the Treatment of Prostate Cancer
Discovery of the Selective CYP17A1 Lyase Inhibitor BMS-351 for the Treatment of Prostate Cancer
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DOI：
10.1021/acsmedchemlett.5b00310
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发表时间：
2016-01-01
影响因子：
4.2
通讯作者：
Balog, Aaron
中科院分区：
文献类型：
--
作者：
Huang, Audris;Jayaraman, Lata;Balog, Aaron
努力鉴定一种有效的、可逆的、非甾体CYP 17 A1裂解酶抑制剂，其对CYP 17 A1羟化酶和CYP 11B 1和21 A2具有良好的选择性，用于治疗去势抵抗性前列腺癌（CRPC），最终发现了BMS-351（化合物18），一种具有优异的体内特性的吡啶基联芳基苯并咪唑。在去势食蟹猴中以1.5 mg剂量对BMS-351进行的生物学评价显示睾酮水平显著降低，糖皮质激素和盐皮质激素干扰最小。基于有利的特征，选择BMS-351作为进一步临床前评价的候选药物。
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.