Abstract
A series of conformationally constrained tri-substituted ureas were synthesized, and their potential as glucagon receptor antagonists was evaluated. This effort resulted in the identification of compound 4a, which had a binding IC50 of 4.0 nM and was shown to reduce blood glucose levels at 3 mg/kg in glucagon-challenged mice containing a humanized glucagon receptor. Compound 4a was efficacious in correcting hyperglycemia induced by a high fat diet in transgenic mice at an oral dose as low as 3 mg/kg.
MeSH terms
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Animals
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Blood Glucose / metabolism
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CHO Cells
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Chromatography, High Pressure Liquid
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Cricetinae
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Cricetulus
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Cyclic AMP / metabolism
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Dietary Fats
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Drug Design
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Gastric Inhibitory Polypeptide / metabolism
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Glucagon / antagonists & inhibitors
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Half-Life
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Humans
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Hyperglycemia / chemically induced
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Hyperglycemia / prevention & control
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Indicators and Reagents
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Mice
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Mice, Transgenic
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Molecular Conformation
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Receptors, Glucagon / antagonists & inhibitors*
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Receptors, Glucagon / genetics
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Urea / analogs & derivatives*
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Urea / chemical synthesis*
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Urea / pharmacology
Substances
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Blood Glucose
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Dietary Fats
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Indicators and Reagents
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Receptors, Glucagon
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Gastric Inhibitory Polypeptide
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Urea
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Glucagon
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Cyclic AMP