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.

青光眼性失明主要由视网膜神经节细胞（Retinal Ganglion Cell, RGC）凋亡所引发。一款既能有效降低眼内压（Intraocular Pressure, IOP），又能同时抑制视网膜神经节细胞凋亡的药物，可为青光眼治疗提供全新的整体解决方案。本研究开发了一类新型含一氧化氮供体（Nitric Oxide Donor, NO-donor）的人类碳酸酐酶II（human Carbonic Anhydrase II, hCA II）抑制剂，以实现双重功能：通过抑制hCA II减少房水生成以降低IOP，同时通过释放一氧化氮提升房水外流。实验结果显示，双靶点化合物A1在急性和慢性高IOP模型中均优于其单靶点对照化合物及阳性对照药物布林佐胺，展现出更优异的降IOP效果，且未观察到显著的体外或体内毒性。尤为值得关注的是，化合物A1可通过减轻氧化应激、抑制星形胶质细胞活化及NLRP3炎症小体激活的途径，减少视网膜神经节细胞凋亡。眼部代谢研究进一步阐明了化合物A1的体内代谢通路。凭借其协同的抗青光眼及视网膜神经节细胞保护作用，化合物A1有望成为全面治疗青光眼的候选药物。