Article

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.

Metabolic Center for Excellence in Drug Discovery, GlaxoSmithKline, 5 Moore Drive, PO Box 13398, Research Triangle Park, NC 27705, USA.
Bioorganic & medicinal chemistry letters (impact factor: 2.65). 01/2009; 19(4):1177-82. DOI:10.1016/j.bmcl.2008.12.085 pp.1177-82
Source: PubMed

ABSTRACT 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.

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Keywords

AMP site
 
glycogen phosphorylase
 
GPa
 
Key binding interactions
 
phenyl urea moieties
 
single nanomolar potency
 
X-ray crystallography studies