Properties of ICI 128,436, a novel aldose reductase inhibitor, and its effects on diabetic complications in the rat.
ICI 128,436 (3-(4-bromo-2-fluorobenzyl)-4-oxo-3H-phthalazin-1-ylacetic acid) is a chemically novel, potent inhibitor of aldose reductase. It inhibits partially purified aldose reductase isolated from a number of sources including human tissue (human lens - IC50 2.0 X 10(-8) mol/L). Dulcitol accumulation in erythrocytes and sciatic nerves of galactose loaded rats was inhibited by five days of treatment with ICI 128,436 (oral ED50's 2.21 mg/kg and 8.56 mg/kg, respectively). On oral administration for five days to streptozotocin diabetic rats, ICI 128,436, reduced sorbitol levels in sciatic nerve, lens, retina, and renal cortex. The ED50 for inhibition of nerve sorbitol accumulation was 5 mg/kg. The effect of a single dose of ICI 128,436 in diabetic rats was prolonged, with little increase in nerve sorbitol for 48 hours. No tolerance to the ability of ICI 128,436 to reduce nerve sorbitol was found on treatment for 74 days. ICI 128,436 was effective in rodent models of the neural and lenticular complications of diabetes. At doses as low as 25 mg/kg/d it completely prevented the development of cataracts in diabetic rats. The deterioration in motor nerve conduction velocity velocity found in diabetic rats was ameliorated by treatment with ICI 128,436 (3.125 mg/kg/d). Thus, ICI 128,436 constitutes a chemically novel aldose reductase inhibitor that is now being assessed for therapeutic value in the diabetic patient.
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D002386:Cataract / Q000209:etiology / Q000517:prevention & control*; D002417:Cattle; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D004285:Dogs; D004912:Erythrocytes / Q000378:metabolism; D005632:Fructose / Q000378:metabolism; D004376:Galactitol / Q000097:blood / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism; D007908:Lens, Crystalline / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009046:Motor Neurons / Q000187:drug effects; D009431:Neural Conduction / Q000187:drug effects*; D010793:Phthalazines / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology*; D051381:Rats; D012160:Retina / Q000187:drug effects / Q000378:metabolism; D012584:Sciatic Nerve / Q000187:drug effects / Q000378:metabolism; D013012:Sorbitol / Q000378:metabolism; D013401:Sugar Alcohol Dehydrogenases / Q000037:antagonists & inhibitors*
D010793:Phthalazines; D011724:Pyridazines; D004376:Galactitol; C042829:ponalrestat; D005632:Fructose; D013012:Sorbitol; D013401:Sugar Alcohol Dehydrogenases; D000449:Aldehyde Reductase