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

GP-1447 {3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]-5- methylphenyla cetic acid}, a novel aldose reductase (AR) inhibitor, exhibited highly potent and specific inhibition of AR activity from human placenta, hu man 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 beta-NADPH and inhibition of AR by GP-1447. In c ontrast to epalrestat, AR activity inhibited by GP-1447 did not recove r after dialysis for 24 hr. Administration of GP-1447 to streptozotoci n (STZ)-induced diabetic rats for 5 days beginning 1 week after STZ in jection effectively inhibited the accumulation of sorbitol in the scia tic nerve, lens and retina with ED(50), values of 0.25, 1.6 and 2.9 mg /kg/day, respectively. The motor nerve conduction velocity (MCV) in ST Z-induced diabetic rats was significantly decreased 4 weeks after the induction of diabetes. Treatment with GP-1447 for the following 2 week s dose-dependently restored the decreased MCV with an ED(50) value of 0.28 mg/kg/day. Administration of GP-1447 (3 and 15 mg/kg/day for 12 w eeks beginning 3 days after STZ injection) completely prevented catara ct formation and was accompanied by marked inhibition of sorbitol accu mulation in the lens. Furthermore, partial reversibility of cataract f ormation and morphological changes of the lens was observed in diabeti c rats treated with 15 mg/kg/day of GP-1447 for 5 weeks beginning 8 we eks after the induction of diabetes. From these results, GP-1447 would be expected to exert potent ameliorating effects on some diabetic com plications. Potent inhibition of cataract formation will be one of the characteristics of this compound.