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  • Title: Pyridones as glucokinase activators: identification of a unique metabolic liability of the 4-sulfonyl-2-pyridone heterocycle.
    Author: Pfefferkorn JA, Lou J, Minich ML, Filipski KJ, He M, Zhou R, Ahmed S, Benbow J, Perez AG, Tu M, Litchfield J, Sharma R, Metzler K, Bourbonais F, Huang C, Beebe DA, Oates PJ.
    Journal: Bioorg Med Chem Lett; 2009 Jun 15; 19(12):3247-52. PubMed ID: 19435665.
    Abstract:
    A promising area of novel anti-diabetic therapy involves identification of small molecule activators of the glucokinase enzyme to reduce blood glucose and normalize glucose stimulated insulin secretion. Herein, we report the identification and optimization of a series of 4-sulfonyl-2-pyridone activators. The activators were evaluated for in vitro biochemical activation and pharmacokinetic properties. As part of these efforts, a unique metabolic liability of the 4-sulfonyl-2-pyridone ring system was identified wherein this heterocycle readily undergoes conjugation with glutathione under non-enzymatic conditions.
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