State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, P. R. China.
State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, P. R. China.
J Med Chem. 2022 Sep 8;65(17):11745-11758. doi: 10.1021/acs.jmedchem.2c00600. Epub 2022 Aug 25.
Based on the synergistic therapeutic effect of nitric oxide (NO) and Rho-associated protein kinase (ROCK) inhibitors on glaucoma, a new group of NO-donating ripasudil derivatives - was designed, synthesized, and biologically evaluated. The results demonstrated that the most active compound maintained potent ROCK inhibitory and NO releasing abilities, reversibly depolymerized F-actin, and suppressed mitochondrial respiration in human trabecular meshwork (HTM) cells. Topical administration of (0.26%) in chronic ocular hypertension glaucoma mice exhibited significant IOP lowering and visual function and retinal ganglion cell (RGC) protection activities, superior to an equal molar dose of ripasudil. could be a promising agent for glaucoma or ocular hypertension, warranting further investigation.
基于一氧化氮 (NO) 和 Rho 相关蛋白激酶 (ROCK) 抑制剂对青光眼的协同治疗效果，设计、合成并生物评价了一组新的 NO 供体型利匹司特衍生物。结果表明，最活性化合物保持了强大的 ROCK 抑制和 NO 释放能力，可使 F-肌动蛋白可逆解聚，并抑制人眼小梁网 (HTM) 细胞中的线粒体呼吸。在慢性高眼压青光眼小鼠中，局部给予 （0.26%）可显著降低眼压，改善视觉功能和视网膜神经节细胞 (RGC) 保护作用，优于等摩尔剂量的利匹司特。因此， 可能是一种有前途的青光眼或高眼压治疗药物，值得进一步研究。
