Abstract
A modestly active, nonselective triarylimidazole lead was optimized for binding affinity with the human glucagon receptor. This led to the identification of a 2- and/or 4-alkyl or alkyloxy substituent on the imidazole C4-aryl group as a structural determinant for significant enhancement in binding with the glucagon receptor (e.g., 41, IC(50)=0.053 microM) and selectivity (>1000x) over p38MAP kinase in this class of compounds.
MeSH terms
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Animals
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CHO Cells
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Cricetinae
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Drug Design
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Drug Evaluation, Preclinical
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Humans
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Imidazoles / chemistry
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Inhibitory Concentration 50
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Magnesium / metabolism
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Magnesium / pharmacology
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Mitogen-Activated Protein Kinases / drug effects
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Mitogen-Activated Protein Kinases / metabolism
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Pyridines / chemistry*
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Pyridines / metabolism
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Pyridines / pharmacology*
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Receptors, Glucagon / antagonists & inhibitors*
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Receptors, Glucagon / metabolism
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Structure-Activity Relationship
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p38 Mitogen-Activated Protein Kinases
Substances
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Imidazoles
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Pyridines
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Receptors, Glucagon
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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Magnesium