Identification of Nitric Oxide-Donating Ripasudil Derivatives with Intraocular Pressure Lowering and Retinal Ganglion Cell Protection Activities

  • J Med Chem. 2022 Sep 8;65(17):11745-11758. doi: 10.1021/acs.jmedchem.2c00600.
Zeqiu Yang  1  2 ,  Jianbing Wu  2 ,  Keling Wu  1 ,  Jingyi Luo  1 ,  Cunrui Li  2 ,  Jiaming Zhang  1  2 ,  Minglei Zhao  1 ,  Tingfang Mei  1  3 ,  Xinqi Liu  1 ,  Bizhi Shang  1 ,  Yihua Zhang  2 ,  Ling Zhao  1 ,  Zhangjian Huang  2
Affiliations
  • 1. State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, P. R. 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, P. R. China.
  • 3. Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510000, P. R. China.
PMID: 36007247 DOI: 10.1021/acs.jmedchem.2c00600
Abstract

Based on the synergistic therapeutic effect of nitric oxide (NO) and Rho-associated protein kinase (ROCK) inhibitors on glaucoma, a new group of NO-donating ripasudil derivatives RNO-1-RNO-6 was designed, synthesized, and biologically evaluated. The results demonstrated that the most active compound RNO-6 maintained potent ROCK inhibitory and NO releasing abilities, reversibly depolymerized F-actin, and suppressed mitochondrial respiration in human trabecular meshwork (HTM) cells. Topical administration of RNO-6 (0.26%) in chronic ocular hypertension glaucoma mice exhibited significant IOP lowering and visual function and retinal ganglion cell (RGC) protection activities, superior to an equal molar dose of ripasudil. RNO-6 could be a promising agent for glaucoma or ocular hypertension, warranting further investigation.

Products