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

• 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)
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2007.05.013

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.