1. Discovery of Novel N-Substituted Prolinamido Indazoles as Potent Rho Kinase Inhibitors and Vasorelaxation Agents
- Author
-
Ying Yang, Xiaoyu Liu, Tianyi Yuan, Xiaozhen Jiao, Renze Li, Xiaoyu Li, Yangyang Yao, Ping Xie, Lianhua Fang, Feilong Yang, Guanhua Du, and Xiang Shi
- Subjects
0301 basic medicine ,Indazoles ,Stereochemistry ,Vasodilator Agents ,Substituent ,Pharmaceutical Science ,Inhibitory postsynaptic potential ,Article ,Analytical Chemistry ,Rho kinase ,inhibitor ,N-substituted prolinamido indazoles ,vasorelaxant ,SAR ,lcsh:QD241-441 ,03 medical and health sciences ,chemistry.chemical_compound ,Structure-Activity Relationship ,0302 clinical medicine ,lcsh:Organic chemistry ,Drug Discovery ,Aortic rings ,Moiety ,Animals ,Humans ,Physical and Theoretical Chemistry ,Rho-associated protein kinase ,IC50 ,Protein Kinase Inhibitors ,Indazole ,rho-Associated Kinases ,Molecular Structure ,Organic Chemistry ,Fasudil ,Molecular Docking Simulation ,030104 developmental biology ,chemistry ,Chemistry (miscellaneous) ,030220 oncology & carcinogenesis ,Drug Design ,Molecular Medicine - 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.
- Published
- 2017