文献类型：期刊文献

英文题名：Design and Synthesis of Small Molecule RhoA Inhibitors: A New Promising Therapy for Cardiovascular Diseases?

作者：Deng, Jing[1];Feng, Enguang[2];Ma, Sheng[3];Zhang, Yan[3];Liu, Xiaofeng[1];Li, Honglin[1];Huang, Huang[1];Zhu, Jin[1];Zhu, Weiliang[2];Shen, Xu[1,2];Miao, Liyan[3];Liu, Hong[2];Jiang, Hualiang[1,2];Li, Jian[1]

机构：[1]E China Univ Sci & Technol, Sch Pharm, Shanghai 200237, Peoples R China;[2]Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China;[3]Soochow Univ, Affiliated Hosp 1, Dept Clin Pharmacol, Res Lab, Suzhou 215006, Peoples R China

年份：2011

卷号：54

期号：13

起止页码：4508

外文期刊名：JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000292479600015)】；

基金：We gratefully acknowledge the financial supports from the National Natural Science Foundation of China (Grants 90813005 and 20902022), National S&T Major Project, China (Grant 2009ZX09501-001 and 2011ZX09102-005-02), the Natural Science Foundation of Jiangsu Province (Grant BK2008172), the 111 Project (Grant B07023), and the Fundamental Research Funds for the Central Universities.

语种：英文

摘要：RhoA is a member of Rho GTPases, a subgroup of the Ras superfamily of small GTP-binding proteins. RhoA, as important regulator of diverse cellular signaling pathways, plays significant roles in cytoskeletal organization, transcription, and cell-cycle progression. The RhoA/ROCK inhibitors have emerged as a new promising treatment for cardiovascular diseases. However, to date, RhoA inhibitors are macromolecules, and to our knowledge, small molecular-based inhibitors have not been reported. In this study, a series of first-in-class small molecular RhoA inhibitors have been discovered by using structure-based virtual screening in conjunction with chemical synthesis and bioassay. Virtual screening of similar to 200,000 compounds, followed by SPR-based binding affinity assays resulted in three compounds with binding affinities to RhoA at the micromolar level (compounds 1-3). Compound 1 was selected for further structure modifications in considering binding activity and synthesis ease. Fourty-one new compounds (1, 12a-v, 13a-h, and 14a-j) were designed and synthesized accordingly. It was found that eight (12a, 12j, 14a, 14b, 14d, 14e, 14 g, and 14h) showed high RhoA inhibition activities with IC(50) values of 1.24 to 3.00 mu M. A pharmacological assay indicated that two compounds (14g and 14 h) demonstrated noticeable vasorelaxation effects against PE-induced contraction in thoracic aorta artery rings and served as good leads for developing more potent cardiovascular agents.