Molecules, Vol. 22, Pages 1766: Discovery of Novel N-Substituted Prolinamido Indazoles as Potent Rho Kinase Inhibitors and Vasorelaxation Agents (Molecules)

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 ?M). 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 ?M) and 4b (IC50 0.17 ?M), 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 ?-proline moiety have improved activity against ROCK I relative to analogues bearing an ?-proline moiety, and among the series of the derivatives with a ?-proline-derived indazole scaffold, the inhibitory activity of the target compounds with a benzyl substituent is superior to those with a benzoyl substituent.