Integration of optimized substituent patterns to produce highly potent 4-aryl-pyridine glucagon receptor antagonists

Abstract Optimized substituent patterns in 4-aryl-pyridine glucagon receptor antagonists were merged to produce highly potent derivatives containing both a 3-[(1 R )-hydroxyethyl] and a 2′-hydroxy group. Due to restricted rotation of the phenyl–pyridine bond, these analogues exist as four isomers. A diastereoselective methylcopper reaction was developed to facilitate the synthesis, and single isomers were isolated with activities in the range IC 50 =10–25 nM.