Identification of Nitric Oxide-Donating Ripasudil Derivatives with Intraocular Pressure Lowering and Retinal Ganglion Cell Protection Activities.
Yang Z, Wu J, Wu K, Luo J, Li C, Zhang J, Zhao M, Mei T, Liu X, Shang B, Zhang Y, Zhao L, Huang Z.
Based on the synergistic therapeutic effect of nitric oxide (NO) and Rho-associated protein kinase (ROCK) inhibitors on glaucoma, a new group of NO-donating ripasudil derivatives <b>RNO-1</b>-<b>RNO-6</b> was designed, synthesized, and biologically evaluated. The results demonstrated that the most active compound <b>RNO-6</b> maintained potent ROCK inhibitory and NO releasing abilities, reversibly depolymerized F-actin, and suppressed mitochondrial respiration in human trabecular meshwork (HTM) cells. Topical administration of <b>RNO-6</b> (0.26%) in chronic ocular hypertension glaucoma mice exhibited significant IOP lowering and visual function and retinal ganglion cell (RGC) protection activities, superior to an equal molar dose of ripasudil. <b>RNO-6</b> could be a promising agent for glaucoma or ocular hypertension, warranting further investigation.