发现吲唑醛固酮合酶（CYP11B2）抑制剂作为高血压的潜在治疗方法。

Discovery of indazole aldosterone synthase (CYP11B2) inhibitors as potential treatments for hypertension.

作者信息

Hoyt Scott B, Taylor Jerry, London Clare, Ali Amjad, Ujjainwalla Feroze, Tata Jim, Struthers Mary, Cully Doris, Wisniewski Tom, Ren Ning, Bopp Charlene, Sok Andrea, Verras Andreas, McMasters Daniel, Chen Qing, Tung Elaine, Tang Wei, Salituro Gino, Clemas Joe, Zhou Gaochao, MacNeil Douglas, Duffy Ruth, Xiong Yusheng

机构信息

Merck Research Laboratories, PO Box 2000, NJ 07065, Rahway, United States.

出版信息

Bioorg Med Chem Lett. 2017 Jun 1;27(11):2384-2388. doi: 10.1016/j.bmcl.2017.04.021. Epub 2017 Apr 8.

DOI:10.1016/j.bmcl.2017.04.021

PMID:28416132

Abstract

We report the discovery and hit-to-lead optimization of a structurally novel indazole series of CYP11B2 inhibitors. Benchmark compound 34 from this series displays potent inhibition of CYP11B2, high selectivity versus related steroidal and hepatic CYP targets, and lead-like physical and pharmacokinetic properties. On the basis of these and other data, the indazole series was progressed to lead optimization for further refinement.

摘要

我们报告了一种结构新颖的吲唑类CYP11B2抑制剂的发现及从苗头化合物到先导化合物的优化过程。该系列中的基准化合物34对CYP11B2表现出强效抑制作用，对相关甾体和肝脏CYP靶点具有高选择性，且具有类先导物的物理和药代动力学性质。基于这些及其他数据，吲唑系列进入先导化合物优化阶段以进行进一步优化。