Design, Synthesis, and Evaluation of Novel ROCK Inhibitors for Glaucoma Treatment: Insights into In Vitro and In Vivo Efficacy and Safety

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2025-05-08 DOI:10.1021/acs.jmedchem.4c03047

Qiang Li, Cunrui Li, Yuanmin Chang, Mingzhi Su, Rilei Yu, Zhangjian Huang, Yue-Wei Guo, Xin Jin

{"title":"Design, Synthesis, and Evaluation of Novel ROCK Inhibitors for Glaucoma Treatment: Insights into In Vitro and In Vivo Efficacy and Safety","authors":"Qiang Li, Cunrui Li, Yuanmin Chang, Mingzhi Su, Rilei Yu, Zhangjian Huang, Yue-Wei Guo, Xin Jin","doi":"10.1021/acs.jmedchem.4c03047","DOIUrl":null,"url":null,"abstract":"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, D25 and R3, which were designed to optimize selectivity, efficacy, and ocular bioavailability. D25 potently inhibited ROCK1/2 with IC50 values of 47.2 nM and 33.8 nM, respectively, surpassing Netarsudil. Compound R3 had weaker ROCK inhibition but demonstrated favorable lipophilicity (logP) and good selectivity to ROCKs, which enhances its potential and safety for ocular delivery. In human trabecular meshwork (HTM) cells, R3 showed lower cytotoxicity than Netarsudil and effectively mitigated oxidative damage, enhanced cellular integrity, and reduced inflammatory cytokine secretion. In rabbit models, D25 significantly lowered IOP, outperforming (S)-Netarsudil. R3 exhibited weaker IOP-lowering efficacy but better selectivity. D25 is a promising glaucoma treatment candidate, with R3 as a safer alternative for further optimization.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"48 1","pages":""},"PeriodicalIF":6.8000,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1021/acs.jmedchem.4c03047","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}

引用次数: 0

Abstract

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, D25 and R3, which were designed to optimize selectivity, efficacy, and ocular bioavailability. D25 potently inhibited ROCK1/2 with IC₅₀ values of 47.2 nM and 33.8 nM, respectively, surpassing Netarsudil. Compound R3 had weaker ROCK inhibition but demonstrated favorable lipophilicity (logP) and good selectivity to ROCKs, which enhances its potential and safety for ocular delivery. In human trabecular meshwork (HTM) cells, R3 showed lower cytotoxicity than Netarsudil and effectively mitigated oxidative damage, enhanced cellular integrity, and reduced inflammatory cytokine secretion. In rabbit models, D25 significantly lowered IOP, outperforming (S)-Netarsudil. R3 exhibited weaker IOP-lowering efficacy but better selectivity. D25 is a promising glaucoma treatment candidate, with R3 as a safer alternative for further optimization.

Abstract Image

查看原文本刊更多论文

用于青光眼治疗的新型ROCK抑制剂的设计、合成和评价：对体外和体内疗效和安全性的见解

抑制rho相关的卷曲激酶（ROCK）已成为降低眼压（IOP）和治疗青光眼的一种有前途的策略。在这里，我们报道了新的ROCK抑制剂D25和R3的合成和评价，它们被设计为优化选择性、有效性和眼生物利用度。D25对ROCK1/2有较强的抑制作用，IC50值分别为47.2 nM和33.8 nM，优于奈沙地尔。化合物R3对岩石的抑制作用较弱，但对岩石具有良好的亲脂性（logP）和良好的选择性，这增强了其眼给药的潜力和安全性。在人小梁网（HTM）细胞中，R3表现出比奈沙地尔更低的细胞毒性，有效减轻氧化损伤，增强细胞完整性，减少炎症细胞因子分泌。在家兔模型中，D25显著降低IOP，优于(S)-Netarsudil。R3降低io的效果较弱，但选择性较好。D25是一种很有前途的青光眼治疗候选药物，R3是一种更安全的选择，可以进一步优化。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.