Diabetic complications such as cataract formation, retinopathy, and neuropathy are believed to result from high intracellular sorbital concentrations.Since aldose reductase catalyzes the conversion of excess glucose to sorbitol, inhibition of this enzyme represents a clinically useful approach toward the treatment and/or prevention of these complications. Though a large number of compounds have been found to inhibit the enzyme, only a few are potent enough to warrant clinical trial studies. There is therefore the need for more potent inhibitors of the enzyme. A nucleophilic amino acid capable of reversible interactions with aldose reductase inhibitors has been identified at the inhibitor binding site. It is the investigators objective to (a) investigate by C-13 NMR studies if a nucleophilic interaction between the enzyme and its inhibitor occurs by using a C-13 enriched inhibitor; and (b) investigate if increasing the reactivity of an aldose reductase inhibitor towards nucleophilic attack would increase the inhibitory activity of the inhibitor. To test the above hypothesis with the hope of developing potent aldose reductase inhibitors, it is the aim of this proposal to: (1) design compounds related to the known aldose reductase inhibitors alconil and sorbinil but processing electrophilically more reactive centers (such as alpha, beta-unsaturated systems); (2) synthesize the compounds so designed; and (3) determine the IC50 values for the inhibition of rat lens aldose reductase for these compounds and for alconil and sorbinil, and compare these values to determine which is a better inhibitor of the enzymes. The most potent compounds from this study will, in the long-term, be studied in vivo using a diabetic rat model to determine their effectiveness in the prevention and/or treatment of diabetic complications. Results from these studies will add to available data on the structure activity relationships of aldose reductase and hence serve as a guide in the future design of novel aldose reductase inhibitors.
