Aldose reductase has been implicated in the etiology of diabetic complications. A variety of compounds have been observed to inhibit aldose reductase and effective, orally active inhibitors of the enzyme have been investigated for many years. Although several of these compounds have progressed to the clinical level, only one such drug is currently on the market. Due to the limited number of available drugs for the treatment of diabetic complications, a number of rational approaches for the discovery of aldose reductase inhibitors have been taken since the determination of the 3-dimensional structure of the enzyme. In this review, rational approaches such as the molecular modeling of aldose reductase and its complex structure and structure-based drug discovery are presented, following a short summary of known inhibitors.

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Derivatives of 2-hydroxyethyldimethylsulfonium p-toluenesulfonate (1) were evaluated for anti-allergic activity in order to develop the drug for treatment of type I allergic diseases. The IgE-induced rat homologous passive cutaneous anaphylaxis (PCA) was inhibited by some 2-alkoxy and 2-aryloxyethyl sulfonium p-toluenesulfonates. There were some correlations between hydrophobicity or electronic properties (HOMO or charge at the O atom) and anti-allergic activity or acute toxicity. Dimethyl(2-phenoxyethyl)sulfonium p-toluenesulfonate (5) was selected as a second lead compound in the next stage.

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Ab initio quantum chemical calculations have been performed to figure out a hypothetical structure that allows for reversible proton transport among Asp85, Schiff base, and Asp96 in bacteriorhodopsin. As an example of the hypothetical structure, we constructed a model system in which Asp85 and Asp96 are located in the Cs symmetry with respect to a vertical plane containing the N atom of the Schiff base and the O atom of the water molecule bound to the Schiff base. The proton transport reaction usually proceeds with the L→M→N in bacteriorhodopsin. In the present hypothetical structure, both of the proton transports (L→M→N and N→M→L) were revealed to occur reversibly.

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