Optimization of the 4-aryl group of 4-aryl-pyridine glucagon antagonists: development of an efficient, alternative synthesis

A narrow structure–activity relationship was established for the 4-aryl group in 4-aryl-pyridine glucagon antagonists, with only small substituents being well-tolerated, and only at the 3′- and 4′-positions. However, substitution with a 2′-hydroxy group gave a ca. 3-fold increase in activity (e.g., 4′-fluoro-2′-hydroxy analogue 33, IC 50=190 nM). For efficient preparation of 2′-substituted phenylpyridines, a novel synthesis via pyrones and 4-methoxy-pyridines was developed. A narrow structure–activity relationship was established for the 4-aryl group in 4-aryl-pyridine glucagon antagonists. However, substitution with a 2′-hydroxy group gave a ca. 3-fold increase in activity. For efficient preparation of 2′-substituted phenylpyridines, a novel synthesis via pyrones and 4-methoxy-pyridines was developed.