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.
MeSH terms
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Animals
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Blood Glucose / analysis
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Combinatorial Chemistry Techniques
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Crystallography, X-Ray
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Diabetes Mellitus, Type 2 / drug therapy*
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Disease Models, Animal
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Glycogen Phosphorylase / antagonists & inhibitors*
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Hypoglycemic Agents / blood
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Hypoglycemic Agents / chemical synthesis*
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Hypoglycemic Agents / chemistry
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Hypoglycemic Agents / pharmacology
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Mice
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Molecular Conformation
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Molecular Structure
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Structure-Activity Relationship
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Urea / pharmacology
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ortho-Aminobenzoates / blood
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ortho-Aminobenzoates / chemical synthesis*
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ortho-Aminobenzoates / chemistry
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ortho-Aminobenzoates / pharmacology*
Substances
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Blood Glucose
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Hypoglycemic Agents
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ortho-Aminobenzoates
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Urea
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Glycogen Phosphorylase
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anthranilamide