Zopolrestat is a potent inhibitor of aldose reductase (IC50s = 1.9 and 41 nM for the human placenta and rat lens enzymes, respectively).1 It inhibits sorbitol accumulation in human and rat erythrocytes (IC50s = 370 and 220 nM, respectively). Zopolrestat (50 μM) inhibits ethanol-induced aldose reductase activity and lipid accumulation in HepG2 cells.2 In vivo, zopolrestat (50 mg/kg) reduces sciatic nerve, retina, and lens accumulation of sorbitol in a rat model of diabetes induced by streptozotocin .1 It also reduces protein excretion and maintains lens transparency and myo-inositol content, markers of cataract development, in rats with STZ-induced diabetes when administered at a dose of 100 mg/kg.3 Zopolrestat also inhibits glyoxalase I (GLOI; Ki = 18 μM).4

|1. Mylari, B.L., Larson, E.R., Beyer, T.A., et al. Novel, potent aldose reductase inhibitors: 3,4-Dihydro-4-oxo-3-[[5-(trifluoromethyl)-2-benzothiazolyl] methyl]-1-phthalazineacetic acid (zopolrestat) and congeners. J. Med. Chem. 34(1), 108-122 (1991).|2. Qiu, L., Cai, C., Zhao, X., et al. Inhibition of aldose reductase ameliorates ethanol•induced steatosis in HepG2 cells. Mol. Med. Rep. 15(5), 2732-2736 (2017).|3. Beyer-Mears, A., Mistry, K., Diecke, F.P.J., et al. Zopolrestat prevention of proteinuria, albuminuria and cataractogenesis in diabetes mellitus. Pharmacology 52(5), 292-302 (1996).|4. Zhai, J., Zhang, H., Zhang, L., et al. Zopolrestat as a human glyoxalase•I inhibitor and its structural basis. ChemMedChem 8(9), 1462-1464 (2013).