Discovery of Novel N-Substituted Prolinamido Indazoles as Potent Rho Kinase Inhibitors and Vasorelaxation Agents
AbstractInhibitors 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
Scifeed alert for new publicationsNever miss any articles matching your research from any publisher
- Get alerts for new papers matching your research
- Find out the new papers from selected authors
- Updated daily for 49'000+ journals and 6000+ publishers
- Define your Scifeed now
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.
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(10):1766.Chicago/Turabian Style
Yao, Yangyang; Li, Renze; Liu, Xiaoyu; Yang, Feilong; Yang, Ying; Li, Xiaoyu; Shi, Xiang; Yuan, Tianyi; Fang, Lianhua; Du, Guanhua; Jiao, Xiaozhen; Xie, Ping. 2017. "Discovery of Novel N-Substituted Prolinamido Indazoles as Potent Rho Kinase Inhibitors and Vasorelaxation Agents." Molecules 22, no. 10: 1766.
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.