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Molecules 2017, 22(10), 1766; doi:10.3390/molecules22101766

Discovery of Novel N-Substituted Prolinamido Indazoles as Potent Rho Kinase Inhibitors and Vasorelaxation Agents

1
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
2
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Received: 19 September 2017 / Accepted: 16 October 2017 / Published: 19 October 2017
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Abstract

Inhibitors of Rho kinase (ROCK) have potential therapeutic applicability in a wide range of diseases, such as hypertension, stroke, asthma and glaucoma. In a previous article, we described the lead discovery of DL0805, a new ROCK I inhibitor, showing potent inhibitory activity (IC50 6.7 μM). Herein, we present the lead optimization of compound DL0805, resulting in the discovery of 24- and 39-fold more-active analogues 4a (IC50 0.27 μM) and 4b (IC50 0.17 μM), among other active analogues. Moreover, ex-vivo studies demonstrated that 4a and 4b exhibited comparable vasorelaxant activity to the approved drug fasudil in rat aortic rings. The research of a preliminary structure–activity relationship (SAR) indicated that the target compounds containing a β-proline moiety have improved activity against ROCK I relative to analogues bearing an α-proline moiety, and among the series of the derivatives with a β-proline-derived indazole scaffold, the inhibitory activity of the target compounds with a benzyl substituent is superior to those with a benzoyl substituent. View Full-Text
Keywords: Rho kinase; inhibitor; N-substituted prolinamido indazoles; vasorelaxant; SAR Rho kinase; inhibitor; N-substituted prolinamido indazoles; vasorelaxant; SAR
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MDPI and ACS Style

Yao, Y.; Li, R.; Liu, X.; Yang, F.; Yang, Y.; Li, X.; Shi, X.; Yuan, T.; Fang, L.; Du, G.; Jiao, X.; Xie, P. Discovery of Novel N-Substituted Prolinamido Indazoles as Potent Rho Kinase Inhibitors and Vasorelaxation Agents. Molecules 2017, 22, 1766.

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