发现4-（2-甲氧基苯基）- 1h -吡唑支架的A20是一种有效的选择性ROCK2抑制剂

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-08-29 DOI:10.1016/j.bmcl.2025.130391

Junzheng Wang , Bin Peng , Guodong Liang, Yan Zhao, Xin Gao, Yuting Zhao, Lu Ga, Ruijuan Li, Yuheng Ma

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引用次数: 0

摘要

rho相关蛋白激酶2 （ROCK2）已成为神经系统疾病和纤维化等疾病的有希望的治疗靶点。本研究基于先导化合物M214与ROCK2的结合方式对其结构进行了优化，化合物A20与4-（2-甲氧基苯基）- 1h -吡唑支架具有较强的抑制ROCK2活性，IC50值为0.18 μM，抑制ROCK1的IC50值为3.0 μM。分子对接研究表明，A20的吡唑环与ROCK2的Met172和Glu170之间的氢键相互作用对增强抑制活性起关键作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Discovery of A20 with 4-(2-methoxyphenyl)-1H-pyrazole scaffold as a potent and selective ROCK2 inhibitor

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Discovery of A20 with 4-(2-methoxyphenyl)-1H-pyrazole scaffold as a potent and selective ROCK2 inhibitor

Rho-associated protein kinase 2 (ROCK2) has become a promising therapeutic target for diseases such as neurological disorders and fibrosis. In this study, structural optimization based on the binding mode of lead compound M214 and ROCK2 was conducted and compound A20 with a 4-(2-methoxyphenyl)-1H-pyrazole scaffold exhibited superior inhibitory activity against ROCK2 with IC₅₀ value of 0.18 μM and inhibited ROCK1 with IC₅₀ value of 3.0 μM. Molecular docking study showed that hydrogen bond interactions between pyrazole ring of A20 and Met172 and Glu170 of ROCK2 played key roles in enhancing inhibitory activity.

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来源期刊

Bioorganic & Medicinal Chemistry Letters 医学-医药化学

CiteScore

5.70

自引率

3.70%

发文量

463

审稿时长

27 days

期刊介绍： Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.