Effects of a Novel Potent Aldose Reductase Inhibitor, GP-1447, on Aldose Reductase Activity In Vitro and on Diabetic Neuropathy and Cataract Formation in Rats

Abstract

GP-1447 {3-[(4, 5, 7-trifluorobenzothiazol-2-yl)methyl]-5-methylphenylacetic acid}, a novel aldose reductase (AR)inhibitor, exhibited highly potent and specific inhibition of AR activity from human placenta, human muscle, porcine and rat lens with IC₅₀ values ranging from 3 to 10 nM. Lineweaver-Burk plots revealed non-competitive inhibition between DL-glyceraldehyde or β-NADPH and inhibition of AR by GP-1447. In contrast to epalrestat, AR activity inhibited by GP-1447 did not recover after dialysis for 24 hr. Administration of GP-1447 to streptozotocin (STZ)-induced diabetic rats for 5 days beginning 1 week after STZ injection effectively inhibited the accumulation of sorbitol in the sciatic nerve, lens and retina with ED₅₀ values of 0.25, 1.6 and 2.9 mg/kg/day, respectively. The motor nerve conduction velocity (MCV)in STZ-induced diabetic rats was significantly decreased 4 weeks after the induction of diabetes. Treatment with GP-1447 for the following 2 weeks dose-dependently restored the decreased MCV with an ED₅₀ value of 0.28 mg/kg/day. Administration of GP-1447 (3 and 15 mg/kg/day for 12 weeks beginning 3 days after STZ injection)completely prevented cataract formation and was accompanied by marked inhibition of sorbitol accumulation in the lens. Furthermore, partial reversibility of cataract formation and morphological changes of the lens was observed in diabetic rats treated with 15 mg/kg/day of GP-1447 for 5 weeks beginning 8 weeks after the induction of diabetes. From these results, GP-1447 would be expected to exert potent ameliorating effects on some diabetic complications. Potent inhibition of cataract formation will be one of the characteristics of this compound.