New inhibitors of aldose reductase: anti-oximes of aromatic aldehydes.
Aldose reductase is an NADPH-dependent enzyme which catalyzes the reduction of glucose to sorbitol. Specific potent inhibitors of aldose reductase are of potential pharmacological use because elevated levels of sorbitol produced by this enzyme in lens, peripheral nerve, retina, and renal glomeruli may be responsible for the pathogenesis associated with chronic diabetes. These inhibitors could also serve as probes of the mechanism of action of aldose reductase. anti-Oximes of aromatic aldehydes (e.g., benzaldoxime and 4-fluorobenzaldoxime) have proved to be effective inhibitors of aldose reductase rivaling pharmacological agents currently used to inhibit this enzyme in vivo. The kinetic patterns of inhibition in which benzyl alcohol is used as the oxidizable substrate suggest that the inhibition is due to the formation of a stable ternary complex composed of aldose reductase, NADP+, and the anti-oxime. Analogus ternary complexes are formed at the active site of horse liver alcohol dehydrogenase which is also inhibited by anti-oximes of efficient substrates.
Shen
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Department of Biological Chemistry School of Medicine, University of California, Los Angeles 90024.
Sigman
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D000426:Alcohol Dehydrogenase / Q000037:antagonists & inhibitors; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D000447:Aldehydes / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D002417:Cattle; D007700:Kinetics; D007064:L-Iditol 2-Dehydrogenase / Q000037:antagonists & inhibitors; D007908:Lens, Crystalline / Q000201:enzymology; D015394:Molecular Structure; D010091:Oximes / Q000138:chemical synthesis / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology
D000447:Aldehydes; D010091:Oximes; D011720:Pyrazoles; D000426:Alcohol Dehydrogenase; D007064:L-Iditol 2-Dehydrogenase; D000449:Aldehyde Reductase