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

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The discovery of BMS-737 as a potent, CYP17 lyase-selective inhibitor for the treatment of castration-resistant prostate cancer
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2022-08-27 , DOI: 10.1016/j.bmcl.2022.128951
Chetan Padmakar Darne ₁ , Upender Velaparthi ₁ , Mark Saulnier ₁ , David Frennesson ₁ , Peiying Liu ₁ , Audris Huang ₁ , John Tokarski ₁ , Aberra Fura ₁ , Thomas Spires ₁ , John Newitt ₁ , Vanessa M Spires ₁ , Mary T Obermeier ₁ , Paul A Elzinga ₁ , Marco M Gottardis ₁ , Lata Jayaraman ₁ , Gregory D Vite ₁ , Aaron Balog ₁

Affiliation

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.

中文翻译：

发现 BMS-737 作为一种有效的 CYP17 裂解酶选择性抑制剂，用于治疗去势抵抗性前列腺癌

我们在此报告了 BMS-737（化合物33）作为一种有效的、非甾体、可逆的小分子抑制剂的发现，证明 CYP17 裂解酶的选择性比 CYP17 羟化酶高 11 倍，以及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1进行了广泛的 SAR 研究，从而鉴定出 BMS-737，这表明在 1-1 中，食蟹猴的盐皮质激素和糖皮质激素水平显着降低了 83%，而没有任何显着的扰动。天 PK/PD 研究。

更新日期：2022-08-29

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