Modified 3-alkyl-1,8-dibenzylxanthines as GTP-competitive inhibitors of phosphoenolpyruvate carboxykinase.
The first non-substrate like inhibitors of human cytosolic phosphoenolpyruvate carboxykinase (PEPCK) competitive with GTP are reported. An effort to discover orally active compounds that improve glucose homeostasis in Type 2 diabetics by reversibly inhibiting PEPCK led to the discovery of 1-allyl-3-butyl-8-methylxanthine (5). We now report modifications at N-1 and C-8 that improved the in vitro activity of the initial xanthine HTS hit by 100-fold and a developing SAR for this class of inhibitor.
D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D006160:Guanosine Triphosphate; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D005947:Glucose