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[Aldose reductase inhibitors].

P Dostert, M Strolin Benedetti

    Journal De Pharmacologie
    |October 1, 1986
    PubMed
    Summary

    Aldose reductase (AR) inhibitors may prevent cataracts by blocking sorbitol buildup and oxidative damage in the eye lens. This study reviews different AR inhibitor classes and their structure-activity relationships.

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    Area of Science:

    • Biochemistry
    • Enzymology
    • Ophthalmology

    Context:

    • Diabetes mellitus can lead to elevated polyol levels in the eye lens, contributing to cataract formation via osmotic stress.
    • Oxidative stress from monosaccharide autoxidation is implicated in lens protein denaturation and glutathione depletion during cataractogenesis.
    • Aldose reductase (AR) plays a key role in polyol pathway metabolism, making it a therapeutic target for preventing diabetic complications.

    Purpose:

    • To review the different classes of aldose reductase inhibitors.
    • To explore the structure-activity relationships (SAR) of these inhibitors.
    • To discuss the potential for a common binding site for AR inhibitors and species/tissue-specific differences in inhibition.

    Summary:

    • Aldose reductase (AR) inhibitors offer a potential strategy to mitigate cataract formation by preventing sorbitol accumulation and associated osmotic stress in the lens.
    • Two proposed mechanisms for AR inhibitors in cataract prevention include counteracting polyol accumulation and trapping radical intermediates to prevent oxidative damage.
    • Three main classes of AR inhibitors are discussed: flavonoids, spirohydantoins (e.g., sorbinil), and compounds with acidic functions (e.g., alrestatine), with an analysis of their SAR.

    Impact:

    • Understanding SAR of AR inhibitors can guide the development of more effective therapeutic agents for diabetic cataracts.
    • Identifying a common binding site could lead to the design of more potent and selective AR inhibitors.
    • Investigating species and tissue variations in AR inhibition is crucial for predicting drug efficacy and optimizing treatment strategies in diverse patient populations.

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