Anthranilimide based glycogen phosphorylase inhibitors for the treatment of type 2 diabetes. Part 3: X-ray crystallographic characterization, core and urea optimization and in vivo efficacy

Key binding interactions of the anthranilimide based glycogen phosphorylase a (GPa) inhibitor 2 from X-ray crystallography studies are described. This series of compounds bind to the AMP site of GP. Using the binding information the core and the phenyl urea moieties were optimized. This work culminated in the identification of compounds with single nanomolar potency as well as in vivo efficacy in a diabetic model.

Graphical abstractUse of an X-ray crystal structure allowed for the optimization of the anthranilimide-based glycogen phosphorylase inhibitors to give compound 23 which displayed both in vitro potency versus GPa and in vivo efficacy in a mouse model of type 2 diabetes.Figure optionsDownload full-size imageDownload as PowerPoint slide