Inhibition of hexonate dehydrogenase and aldose reductase from bovine retina by sorbinil, statil, M79175 and valproate.
Aldose reductase inhibitors (A.R.I.s), developed as potentially therapeutic agents for the treatment of complications of long-term diabetes, were found to be potent inhibitors of aldose reductase (ALR2) partially purified from bovine retina (IC50 values: Statil 0.89 microM, Sorbinil 2 microM, M79175 greater than 1 microM). These compounds varied, however, in their ability to inhibit hexonate dehydrogenase (ALR1), a closely related enzyme isolated from the same source (IC50 values: Statil greater than 1 microM, Sorbinil 3.9 microM, M79175 0.18 microM). Statil and Sorbinil were active against ALR2 at very low concentrations (approx. 5% inhibition at 100 pM), but did not inhibit ALR1 at less than or equal to 10 nM. In contrast, M79175 (structurally very similar to Sorbinil) and M7HEQ (a flavonoid) were preferential inhibitors of ALR1. Valproate, a compound of value in the treatment of epilepsies, was a poor inhibitor of ALR2 (18% at 1 mM). Furthermore, valproate was found to be a relatively poor inhibitor of ALR1, particularly in comparison with M79175.
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D000818:Animals; D002237:Carbohydrate Dehydrogenases / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D002417:Cattle; D007093:Imidazoles / Q000494:pharmacology*; D048289:Imidazolidines; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008968:Molecular Conformation; D010793:Phthalazines / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology*; D012160:Retina / Q000201:enzymology*; D013401:Sugar Alcohol Dehydrogenases / Q000037:antagonists & inhibitors*; D014635:Valproic Acid / Q000494:pharmacology*; D014812:Vitamin K / Q000378:metabolism
D007093:Imidazoles; D048289:Imidazolidines; D010793:Phthalazines; D011724:Pyridazines; D014812:Vitamin K; C042829:ponalrestat; D014635:Valproic Acid; C037070:M 79175; D002237:Carbohydrate Dehydrogenases; D013401:Sugar Alcohol Dehydrogenases; C020590:L-glucuronate reductase; D000449:Aldehyde Reductase; C026411:sorbinil