| 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. | |
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MedLine Citation:
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PMID: 20829042 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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 |
Publication Detail:
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Type: Journal Article Date: 2010-08-21 |
Journal Detail:
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Title: Bioorganic & medicinal chemistry letters Volume: 20 ISSN: 1464-3405 ISO Abbreviation: Bioorg. Med. Chem. Lett. Publication Date: 2010 Nov |
Date Detail:
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Created Date: 2010-10-11 Completed Date: 2011-01-24 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9107377 Medline TA: Bioorg Med Chem Lett Country: England |
Other Details:
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Languages: eng Pagination: 6262-7 Citation Subset: IM |
Copyright Information:
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Copyright © 2010 Elsevier Ltd. All rights reserved. |
Affiliation:
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Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, United States. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Catalysis Chromatography, Ion Exchange Cytosol / drug effects, enzymology, metabolism Enzyme Activators / chemistry*, pharmacology* Glucokinase / drug effects*, metabolism* Glutathione / metabolism* Glutathione Transferase / metabolism* Humans Injections, Intravenous Mass Spectrometry Microsomes, Liver / drug effects, enzymology, metabolism Pyridones / chemistry*, pharmacology* Rats Spectrophotometry, Ultraviolet Sulfides / chemistry*, pharmacology* |
| Chemical | |
Reg. No./Substance:
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0/Enzyme Activators; 0/Pyridones; 0/Sulfides; 70-18-8/Glutathione; EC 2.5.1.18/Glutathione Transferase; EC 2.7.1.2/Glucokinase |
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