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Abstract #121583 Published in IGR 25-1
Development of Nitric Oxide-Donating Netarsudil Derivatives as a Synergistic Therapy for Glaucoma with Reduced Ocular Irritation
Li C; Zhu M; Liu S; Zhang J; Ye H; Zhang C; Ji D; Tang H; Zhang Y; Wu J; Huang ZJournal of Medicinal Chemistry 2024; 67: 16311-16327
Based on the synergistic therapeutic effect of nitric oxide (NO) and Rho-associated protein kinase (ROCK) inhibitors on glaucoma, a series of NO-donating Netarsudil derivatives were designed, synthesized, and their activities in vitro and in vivo were evaluated. Among them, ()- released an appropriate amount of NO in aqueous humor in vitro and displayed potent ROCK inhibition. Topical administration of ()- significantly lowered intraocular pressure in an acute ocular hypertension rabbit model and protected retinal ganglion cells in a magnetic microbead occlusion mouse model. A metabolism investigation revealed that ()- released , a metabolite after NO releasing, and , an active metabolite of ()-Netarsudil, in rabbit eyes. Notably, introducing an NO donor moiety attenuated ROCK inhibition-induced ocular irritation in an sGC-independent manner, suggesting that the attenuated conjunctival hyperemia effect of ()- is related to the NO-induced protein S-nitrosation of phosphodiesterase 3A (PDE3A). Overall, ()- is a promising candidate for glaucoma treatment.
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China.
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