Abstract
Optimization of the amino acid residue of a series of anthranilimide-based glycogen phosphorylase inhibitors is described leading to the identification of serine and threonine ether analogs. t-Butylthreonine analog 20 displayed potent in vitro inhibition of GPa, low potential for P450 inhibition, and excellent pharmacokinetic properties.
MeSH terms
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Animals
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Aryl Hydrocarbon Hydroxylases / antagonists & inhibitors*
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Aryl Hydrocarbon Hydroxylases / chemistry
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Chemistry, Pharmaceutical / methods*
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Crystallography, X-Ray
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Cytochrome P-450 CYP2C9
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Diabetes Mellitus, Type 2 / drug therapy*
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Drug Design
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Glycine / chemistry
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Glycogen Phosphorylase / antagonists & inhibitors*
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Glycogen Phosphorylase / metabolism
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Humans
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Imides / chemistry*
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Inhibitory Concentration 50
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Liver / enzymology
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Models, Chemical
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Rats
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Serine / chemistry*
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Threonine / chemistry*
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ortho-Aminobenzoates / chemistry*
Substances
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Imides
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ortho-Aminobenzoates
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Threonine
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Serine
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CYP2C9 protein, human
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Cytochrome P-450 CYP2C9
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Aryl Hydrocarbon Hydroxylases
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Glycogen Phosphorylase
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Glycine