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 (eg, 41, IC50= 0.053 μM) and selectivity (> 1000×) over p38MAP kinase in this class of compounds.
