Discovery of Novel NO–Donor Containing hCA II Inhibitors with Retinal Ganglion Cell-Protective Effects for the Efficient Treatment of Glaucoma

Glaucoma-induced blindness primarily results from RGC apoptosis. A medication capable of effectively reducing IOP while simultaneously preventing RGC apoptosis could offer a holistic approach to glaucoma treatment. In this study, novel NO-donor containing hCA II inhibitors were developed to achieve dual functionality: lowering IOP by decreasing aqueous humor production (via hCA II inhibition) and enhancing outflow (via NO release). The experimental results indicated that the dual-target compound <b>A1</b> outperformed its single-target counterpart and the reference drug brinzolamide in both acute and chronic high IOP models, demonstrating superior IOP-lowering efficacy without notable in vitro or in vivo toxicity. Of particular interest, compound <b>A1</b> reduced RGC apoptosis through mechanisms involving decreased oxidative stress and the suppression of astrocyte and NLRP3 inflammasome activation. Ocular metabolism studies further clarified the in vivo metabolic pathway of compound <b>A1</b>. With its synergistic antiglaucoma and RGCs-protective effects, compound <b>A1</b> represents a promising candidate for comprehensive glaucoma therapy.