Development of potent aldose reductase inhibitors having a hydantoin structure.
Seventeen hydantoin derivatives were tested as inhibitors of aldose reductase, an enzyme believed to participate in the initiation of diabetic complications. Nine compounds with high inhibitory activities (IC50 values against purified rat lens aldose reductase less than or equal to 1.06 X 10(-6)M) were tested further for their abilities to prevent sorbitol accumulation induced by exposure of excised rat lens and sciatic nerve to a high glucose concentration (50 mM). Seven active compounds among them inhibited sorbitol accumulation by about 50% or more at a concentration of 10(-5)M. These seven compounds were given orally to streptozotocin-induced diabetic rats at a dose of 50 mg/kg/day and were assessed for their abilities to prevent both sorbitol accumulation in two tissues (lens and sciatic nerve) and myo-inositol depletion in the sciatic nerve. 1-[(2,4,5-Trichlorophenyl)sulfonyl]hydantoin, 1-[(2,5-dichlorophenyl)sulfonyl]hydantoin, and 1-[(beta-naphthyl)sulfonyl]hydantoin were found to be the most effective: they inhibited sorbitol accumulation in the sciatic nerve completely and that in the lens by more than 92%. It is conceivable from this study that the three compounds are promising for further investigation targeted to the treatment of diabetic complications.
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology; D006827:Hydantoins / Q000138:chemical synthesis / Q000494:pharmacology*; D007294:Inositol / Q000378:metabolism; D007908:Lens, Crystalline / Q000201:enzymology; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains / Q000378:metabolism; D012584:Sciatic Nerve / Q000201:enzymology; D013012:Sorbitol / Q000378:metabolism; D013329:Structure-Activity Relationship; D013401:Sugar Alcohol Dehydrogenases / Q000037:antagonists & inhibitors*
D006827:Hydantoins; D007294:Inositol; D013012:Sorbitol; D013401:Sugar Alcohol Dehydrogenases; D000449:Aldehyde Reductase