C-8 Modifications of 3-alkyl-1,8-dibenzylxanthines as inhibitors of human cytosolic phosphoenolpyruvate carboxykinase

Enzyme and cellular assay results for a number of new modifications on the C-8 aminobenzyl unit are reported. Pyrazole sulfonic acid amide analogs are shown to provide improved inhibitors of cPEPCK and a new π–π interaction with the protein. New modifications on the C-8 4-aminobenzyl unit of the pre...

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Bibliographic Details
Published in:	Bioorganic & medicinal chemistry letters Vol. 17; no. 14; pp. 3835 - 3839
Main Authors:	Pietranico, Sherrie L., Foley, Louise H., Huby, Nicholas, Yun, Weiya, Dunten, Pete, Vermeulen, John, Wang, Ping, Toth, Katherine, Ramsey, Gwendolyn, Gubler, Mary-Lou, Wertheimer, Stanley J.
Format:	Journal Article
Language:	English
Published:	Oxford Elsevier Ltd 15-07-2007 Elsevier
Subjects:	AMIDES BASIC BIOLOGICAL SCIENCES Biological and medical sciences cPEPCK inhibitors Cytosol - enzymology Enzyme and cellular assays ENZYME INHIBITORS Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology ENZYMES General and cellular metabolism. Vitamins Humans Medical sciences Models, Molecular MODIFICATIONS national synchrotron light source Pharmacology. Drug treatments PHOSPHOENOLPYRUVATE Phosphoenolpyruvate Carboxykinase (GTP) - antagonists & inhibitors SULFONAMIDES X-ray Xanthine class Xanthines - chemistry Xanthines - pharmacology Xanthine class Enzyme and cellular assays X-ray cPEPCK inhibitors Purine derivatives Cyclopropane derivatives Nitrogen heterocycle Lyases Binding site Cytosol Modeling Structure activity relation Carboxy-lyases Molecular model Bicyclic compound Xanthine derivatives Chemical synthesis Human Enzyme Benzene derivatives Enzyme inhibitor Inhibitor enzyme complex Organic chlorine compounds Carbon-carbon lyases Organic fluorine compounds Phosphoenolpyruvate carboxykinase (ATP)
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Summary:	Enzyme and cellular assay results for a number of new modifications on the C-8 aminobenzyl unit are reported. Pyrazole sulfonic acid amide analogs are shown to provide improved inhibitors of cPEPCK and a new π–π interaction with the protein. New modifications on the C-8 4-aminobenzyl unit of the previously reported 3-alkyl-1,8-dibenzylxanthine inhibitors of cPEPCK are presented. The most active compound reported here is the 5-chloro-1,3-dimethyl-1 H-pyrazole-4-sulfonic acid amide derivative 2 with an IC 50 of 0.29 ± 0.08 μM. An X-ray analysis of a heteroaromatic sulfonamide is presented showing a new π–π interaction.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 BNL-81179-2008-JA DE-AC02-98CH10886 Doe - Office Of Science
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2007.05.013