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 A1 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 A1 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 A1. With its synergistic antiglaucoma and RGCs-protective effects, compound A1 represents a promising candidate for comprehensive glaucoma therapy.