Development of second-generation small-molecule RhoA inhibitors with enhanced water solubility, tissue potency, and significant in vivo efficacy.
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 IC50 values of 1.17-1.84 μM. 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.
Department of Clinical Pharmacology Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shi Zhi Street, Suzhou 215006 (China).
Sheng
S
Ma
Jing
J
Deng
Baoli
B
Li
Xiujiang
X
Li
Zhaowei
Z
Yan
Jin
J
Zhu
Gang
G
Chen
Zhong
Z
Wang
Hualiang
H
Jiang
Liyan
L
Miao
Jian
J
Li
D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D006801:Humans; D008297:Male; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D012995:Solubility; D013329:Structure-Activity Relationship; D014665:Vasodilator Agents / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D020301:Vasospasm, Intracranial / Q000188:drug therapy / Q000473:pathology; D014867:Water / Q000737:chemistry; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism
D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D014665:Vasodilator Agents; D014867:Water; D020742:rhoA GTP-Binding Protein
RhoA inhibitors; cardiovascular agents; subarachnoid hemorrhage; vasorelaxation; water solubility