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Development of Second‐Generation Small‐Molecule RhoA Inhibitors with Enhanced Water Solubility, Tissue Potency, and Significant in vivo Efficacy
Author(s) -
Ma Sheng,
Deng Jing,
Li Baoli,
Li Xiujiang,
Yan Zhaowei,
Zhu Jin,
Chen Gang,
Wang Zhong,
Jiang Hualiang,
Miao Liyan,
Li Jian
Publication year - 2015
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201402386
Subject(s) - potency , in vivo , rhoa , solubility , chemistry , small molecule , molecule , pharmacology , biophysics , in vitro , nanotechnology , biochemistry , materials science , medicine , biology , organic chemistry , microbiology and biotechnology , signal transduction
RhoA, a member of the Rho GTPases, is involved in a variety of cellular functions and could be a suitable therapeutic target for the treatment of cardiovascular diseases. However, few small‐molecule RhoA inhibitors have been reported. Based on our previously reported lead compounds, 32 new 2‐substituted quinoline (or quinoxaline) derivatives were synthesized and tested in biological assays. Six compounds showed high RhoA inhibitory activities, with IC 50 values of 1.17–1.84 μ M . Among these, ( E )‐3‐(3‐(ethyl(quinolin‐2‐yl)amino)phenyl)acrylic acid ( 26 b ) and ( E )‐3‐(3‐(butyl(quinolin‐2‐yl)amino)phenyl)acrylic acid ( 26 d ) demonstrated noticeable vasorelaxation effects against phenylephrine‐induced contraction in thoracic aorta artery rings, and compound 26 b had good water solubility and showed significant in vivo efficacy, which was similar to that of 5‐(1,4‐diazepane‐1‐sulfonyl)isoquinoline (fasudil) in a subarachnoid hemorrhage–cardiovascular model. To the best of our knowledge, compound 26 b is the first example of a small‐ molecule RhoA inhibitor with potent in vivo efficacy, which could serve as a good lead for designing cardiovascular agents.