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
✍ Scribed by 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
- Publisher
- Elsevier Science
- Year
- 2010
- Tongue
- English
- Weight
- 689 KB
- Volume
- 20
- Category
- Article
- ISSN
- 0960-894X
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✦ Synopsis
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.