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

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

  • J Med Chem. 2025 May 22;68(10):10008-10030. doi: 10.1021/acs.jmedchem.4c03047.
Qiang Li 1 2,  Cunrui Li 3,  Yuanmin Chang 1 2,  Mingzhi Su 2,  Rilei Yu 4,  Zhangjian Huang 3,  Yue-Wei Guo 2 5,  Xin Jin 2
Affiliations

Affiliations

  • 1 Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China.
  • 2 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264117, China.
  • 3 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, China.
  • 4 School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.
  • 5 School of Medicine, Shanghai University, Shanghai 200444, China.
PMID: 40340390 DOI: 10.1021/acs.jmedchem.4c03047
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.

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