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

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-1H-pyrazole-4-sulfonic acid amide derivative 2 with an IC50 of 0.29 ± 0.08 μM. An X-ray analysis of a heteroaromatic sulfonamide is presented showing a new π–π interaction.

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.Figure optionsDownload as PowerPoint slide