Novel pyridyl- or isoquinolinyl-substituted indolines and indoles as potent and selective aldosterone synthase inhibitors.
Novel pyridyl- or isoquinolinyl-substituted indolines and indoles as potent and selective aldosterone synthase inhibitors.
复制标题
DOI：
10.1021/jm500140c
复制
发表时间：
2014-06
影响因子：
7.3
通讯作者：
Lina Yin;Qingzhong Hu;J. Emmerich;M. M. Lo-M.;E. Metzger;Amjad Ali;R. Hartmann
中科院分区：
文献类型：
--
作者：
Lina Yin;Qingzhong Hu;J. Emmerich;M. M. Lo-M.;E. Metzger;Amjad Ali;R. Hartmann
在病理学上，高水平的醛固酮与严重的心血管疾病如充血性心力衰竭、高血压和心肌纤维化相关。抑制醛固酮合成酶（CYP 11B 2）以降低醛固酮水平已被提出作为与CYP 11B 2相关的疾病的有希望的治疗，因为它是醛固酮生物合成中的关键酶。通过配体的方法设计了一系列新的吡啶基或异喹啉基取代的吲哚啉和吲哚。合成的化合物进行了测试，发现是强CYP 11B 2抑制剂。最有效的药物显示IC 50值小于3 nM，与法倔唑和LCI 699的效力相似。其中，化合物14和23对高度同源的CYP 11B 1表现出良好的选择性，选择性因子（SF = IC 50 CYP 11B 1/IC 50 CYP 11B 2）约170;因此，它们上级法倔唑和LCI 699（SF 50 μM）的一组肝促性腺激素酶，包括CYP 1A 2、CYP 2C 9、CYP 2C 19、CYP 2D 6和CYP 3A 4以及关键的类固醇生成酶CYP 17和CYP 19。由于这些有利的特征，化合物14和23被认为是进一步体内评价的候选物。
Pathologically, high levels of aldosterone are associated with severe cardiovascular diseases such as congestive heart failure, hypertension, and myocardial fibrosis. The inhibition of aldosterone synthase (CYP11B2) to reduce aldosterone levels has been proposed as a promising treatment for diseases related to CYP11B2 because it is the crucial enzyme in the biosynthesis of aldosterone. A series of novel pyridyl- or isoquinolinyl-substituted indolines and indoles was designed via a ligand-based approach. The synthesized compounds were tested and found to be strong CYP11B2 inhibitors. The most potent ones showed IC50 values of less than 3 nM, being similarly potent as fadrozole and LCI699. Among them, compounds 14 and 23 showed good selectivity over the highly homologous CYP11B1, with selectivity factors (SF = IC50 CYP11B1/IC50 CYP11B2) around 170; thus, they are superior to fadrozole and LCI699 (SFs 50 μM) of a panel of hepatic CYP enzymes including CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 and the crucial steroidogenic enzymes, CYP17 and CYP19. Because of these advantageous profiles, compounds 14 and 23 are considered to be candidates for further in vivo evaluation.