State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China.
School of Pharmacy, Key Laboratory of Active Components of Xinjiang Natural Medicine and Drug Release Technology, Engineering Research Center of Xinjiang and Central Asian Medicine Resources, Xinjiang Medical University, Urumqi 830054, China.
J Med Chem. 2024 Sep 26;67(18):16311-16327. doi: 10.1021/acs.jmedchem.4c01199. Epub 2024 Aug 20.
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.
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作用，设计、合成了一系列 NO 供体型他喷丁衍生物，并评价了它们的体外和体内活性。其中，()- 在体外房水中释放适量的 NO，并表现出很强的 ROCK 抑制作用。()- 的局部给药显著降低了急性高眼压兔模型的眼内压，并在磁微珠阻塞小鼠模型中保护了视网膜神经节细胞。代谢研究表明，()- 在兔眼中释放出, 一种 NO 释放后的代谢物，以及, 他喷丁的一种活性代谢物。值得注意的是，引入 NO 供体部分以非可溶性鸟苷酸环化酶 (sGC) 依赖的方式减弱了 ROCK 抑制诱导的眼刺激，表明 ()- 的结膜充血作用减弱与 NO 诱导的磷酸二酯酶 3A (PDE3A) 蛋白 S-亚硝基化有关。总的来说，()- 是治疗青光眼的有前途的候选药物。
