Intrinsic electrophilicity of the 4-methylsulfonyl-2-pyridone scaffold in glucokinase activators: Role of glutathione-S-transferases and in vivo quantitation of a glutathione conjugate in rats |
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Authors: | John Litchfield Raman Sharma Karen Atkinson Kevin J Filipski Stephen W Wright Jeffrey A Pfefferkorn Beijing Tan Rachel E Kosa Benjamin Stevens Meihua Tu Amit S Kalgutkar |
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Institution: | Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, United States |
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Abstract: | Previous studies on the in vitro metabolism of 4-alkylsulfonyl-2-pyridone-based glucokinase activators revealed a facile, non-enzymatic displacement of the 4-alkylsulfonyl group by glutathione. In the present studies, a role for glutathione-S-transferases (GST) as catalysts in the desulfonylation reaction was demonstrated using a combination of human liver microsomes, human liver cytosol and human GSTs. The identification of a glutathione conjugate in circulation following intravenous administration of a candidate 4-methylsulfonyl-2-pyridone to rats confirmed the relevance of the in vitro findings. |
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