title: 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.
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.
authors.affiliation: Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, United States.
authors.forename: John
authors.initials: J
authors.lastname: Litchfield
authors.forename: Raman
authors.initials: R
authors.lastname: Sharma
authors.forename: Karen
authors.initials: K
authors.lastname: Atkinson
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Filipski
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Wright
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Pfefferkorn
authors.forename: Beijing
authors.initials: B
authors.lastname: Tan
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Kosa
authors.forename: Benjamin
authors.initials: B
authors.lastname: Stevens
authors.forename: Meihua
authors.initials: M
authors.lastname: Tu
authors.forename: Amit S
authors.initials: AS
authors.lastname: Kalgutkar
mesh_terms: D000818:Animals; D002384:Catalysis; D002852:Chromatography, Ion Exchange; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D020536:Enzyme Activators / Q000737:chemistry* / Q000494:pharmacology*; D005941:Glucokinase / Q000187:drug effects* / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism*; D006801:Humans; D007275:Injections, Intravenous; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D011728:Pyridones / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D013056:Spectrophotometry, Ultraviolet; D013440:Sulfides / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D020536:Enzyme Activators; D011728:Pyridones; D013440:Sulfides; D005982:Glutathione Transferase; D005941:Glucokinase; D005978:Glutathione