Development of Nitric Oxide-Donating Netarsudil Derivatives as a Synergistic Therapy for Glaucoma with Reduced Ocular Irritation,Journal of Medicinal Chemistry

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Development of Nitric Oxide-Donating Netarsudil Derivatives as a Synergistic Therapy for Glaucoma with Reduced Ocular Irritation
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-08-20 , DOI: 10.1021/acs.jmedchem.4c01199
Cunrui Li ₁ , Mingchao Zhu ₁ , Songqi Liu ₁ , Jiaming Zhang ₁ , Hui Ye ₁ , Chen Zhang ₁ , Duorui Ji ₁ , Haoyang Tang ₁ , Yihua Zhang ₁ , Jianbing Wu ₁ , Zhangjian Huang _{1,

2}

Affiliation

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, (S)-10e released an appropriate amount of NO in aqueous humor in vitro and displayed potent ROCK inhibition. Topical administration of (S)-10e 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 (S)-10e released 7a, a metabolite after NO releasing, and 13, an active metabolite of (S)-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 (S)-10e is related to the NO-induced protein S-nitrosation of phosphodiesterase 3A (PDE3A). Overall, (S)-10e is a promising candidate for glaucoma treatment.

中文翻译：

开发提供一氧化氮的奈塔舒地尔衍生物作为青光眼的协同疗法并减少眼部刺激

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供体奈塔舒地尔衍生物，并评价了其体外和体内活性。其中( S ) -10e在体外在房水中释放适量的NO，并表现出有效的ROCK抑制作用。局部施用 ( S ) -10e可显着降低急性高眼压兔模型的眼内压，并保护磁微珠闭塞小鼠模型的视网膜神经节细胞。代谢研究表明，( S ) -10e在兔眼中释放 NO 后释放代谢物7a ，以及 ( S )-Netarsudil 的活性代谢物13 。值得注意的是，引入 NO 供体部分以不依赖 sGC 的方式减弱了 ROCK 抑制诱导的眼部刺激，表明 ( S ) -10e减弱的结膜充血作用与 NO 诱导的磷酸二酯酶 3A (PDE3A) 蛋白 S-亚硝化作用有关。）。总体而言，( S ) -10e是青光眼治疗的有希望的候选者。

更新日期：2024-08-20

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