Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
1373533 | Bioorganic & Medicinal Chemistry Letters | 2010 | 6 Pages |
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.
Graphical abstractThe role of glutathione-S-transferase in the nucleophilic displacement reaction on 4-substituted-2-pyridone derivatives by glutathione (GSH) was examined. The principal in vivo clearance mechanism of 1 in rats involved GSH conjugation leading to the formation of 2.Figure optionsDownload full-size imageDownload as PowerPoint slide