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

• Published in: Bioorganic & medicinal chemistry letters 2010-11, Vol.20 (21), p.6262-6267
• Main Authors: Litchfield, John, Sharma, Raman, Atkinson, Karen, Filipski, Kevin J., Wright, Stephen W., Pfefferkorn, Jeffrey A., Tan, Beijing, Kosa, Rachel E., Stevens, Benjamin, Tu, Meihua, Kalgutkar, Amit S.
• Format: Article
• Language: English
• Subjects: Analysis; Animals; Biological and medical sciences; Catalysis; Chromatography, Ion Exchange; Cytosol; Cytosol - drug effects; Cytosol - enzymology; Cytosol - metabolism; Electrophile; Enzyme Activators - chemistry; Enzyme Activators - pharmacology; General pharmacology; Glucokinase - drug effects; Glucokinase - metabolism; Glutathione; Glutathione - metabolism; Glutathione transferase; Glutathione Transferase - metabolism; Humans; Injections, Intravenous; Mass Spectrometry; Medical sciences; Microsomes; Microsomes, Liver - drug effects; Microsomes, Liver - enzymology; Microsomes, Liver - metabolism; Pharmacokinetics; Pharmacology. Drug treatments; Pyridones - chemistry; Pyridones - pharmacology; Rats; Reactive metabolite; Spectrophotometry, Ultraviolet; Sulfides - chemistry; Sulfides - pharmacology
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.08.095

The 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. 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.