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Abstract #127672 Published in IGR 25-3
Design, Synthesis, and Evaluation of Novel ROCK Inhibitors for Glaucoma Treatment: Insights into In Vitro and In Vivo Efficacy and Safety
Li Q; Li C; Chang Y; Su M; Yu R; Huang Z; Guo YW; Jin XJournal of Medicinal Chemistry 2025; 68: 10008-10030
The inhibition of Rho-associated coiled-coil kinase (ROCK) has emerged as a promising strategy for reducing intraocular pressure (IOP) and treating glaucoma. Here, we report the synthesis and evaluation of novel ROCK inhibitors, and , which were designed to optimize selectivity, efficacy, and ocular bioavailability. potently inhibited ROCK1/2 with IC values of 47.2 nM and 33.8 nM, respectively, surpassing Netarsudil. Compound had weaker ROCK inhibition but demonstrated favorable lipophilicity (log) and good selectivity to ROCKs, which enhances its potential and safety for ocular delivery. In human trabecular meshwork (HTM) cells, showed lower cytotoxicity than Netarsudil and effectively mitigated oxidative damage, enhanced cellular integrity, and reduced inflammatory cytokine secretion. In rabbit models, significantly lowered IOP, outperforming ()-Netarsudil. exhibited weaker IOP-lowering efficacy but better selectivity. is a promising glaucoma treatment candidate, with as a safer alternative for further optimization.
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