Discovery of novel ROCK inhibitors RX-021 and RX-044 with intraocular pressure-lowering effect for glaucoma treatment

  • Eur J Med Chem. 2026 Jun 30:317:119101. doi: 10.1016/j.ejmech.2026.119101.
Guiyan Han  1 ,  Cunrui Li  2 ,  Xiang Chen  3 ,  Mingzhi Su  3 ,  Rilei Yu  4 ,  Zhangjian Huang  5 ,  Yue-Wei Guo  6 ,  Xin Jin  7
Affiliations
  • 1. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264117, China; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, China.
  • 2. 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.
  • 3. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264117, China.
  • 4. School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China.
  • 5. 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; School of Pharmacy, Xinjiang Key Laboratory of Biopharmaceuticals and Medical Devices, 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. Electronic address: [email protected].
  • 6. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264117, China. Electronic address: [email protected].
  • 7. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264117, China. Electronic address: [email protected].
PMID: 42398402 DOI: 10.1016/j.ejmech.2026.119101
Abstract

Through systematic optimization of lead D25, we identified two novel ROCK inhibitors, RX-021 and RX-044. Maintaining DFG interactions while optimizing linker flexibility was critical for potency. RX-044 showed excellent ROCK1/2 inhibition (IC50 = 10.01 and 9.68 nM), favorable kinase selectivity, and no cytotoxicity in HTM cells. In a mouse ocular hypertension model, RX-021 achieved superior IOP reduction (5.38 ± 1.51 mmHg at 4 h) versus (S)-Netarsudil, with sustained 24 h efficacy and reversible HTM cell effects. Both compounds provided significant retinal neuroprotection, preserving retinal ganglion cell survival, restoring electroretinography responses, and ameliorating histopathological changes. Slit-lamp exams confirmed that initial ocular irritation subsided with extended dosing. These findings establish RX-021 and RX-044 as promising novel ROCK inhibitors with enhanced IOP-lowering efficacy and good retinal protective effects for glaucoma therapy.

Keywords
Glaucoma; Intraocular pressure; ROCKs; Retinal.
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