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

Bioorg Med Chem Lett. 2010 Nov 1;20(21):6262-7. doi: 10.1016/j.bmcl.2010.08.095. Epub 2010 Aug 21.

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.

MeSH terms

  • Animals
  • Catalysis
  • Chromatography, Ion Exchange
  • Cytosol / drug effects
  • Cytosol / enzymology
  • Cytosol / metabolism
  • Enzyme Activators / chemistry*
  • Enzyme Activators / pharmacology*
  • Glucokinase / drug effects*
  • Glucokinase / metabolism*
  • Glutathione / metabolism*
  • Glutathione Transferase / metabolism*
  • Humans
  • Injections, Intravenous
  • Mass Spectrometry
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / enzymology
  • Microsomes, Liver / metabolism
  • Pyridones / chemistry*
  • Pyridones / pharmacology*
  • Rats
  • Spectrophotometry, Ultraviolet
  • Sulfides / chemistry*
  • Sulfides / pharmacology*

Substances

  • Enzyme Activators
  • Pyridones
  • Sulfides
  • Glutathione Transferase
  • Glucokinase
  • Glutathione