RESUMO
Optimized substituent patterns in 4-aryl-pyridine glucagon receptor antagonists were merged to produce highly potent derivatives containing both a 3-[(1R)-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.
Assuntos
Compostos de Benzil/química , Compostos de Benzil/farmacologia , Piridinas/química , Piridinas/farmacologia , Receptores de Glucagon/antagonistas & inibidores , Concentração Inibidora 50 , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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, IC50=190 nM). For efficient preparation of 2'-substituted phenylpyridines, a novel synthesis via pyrones and 4-methoxy-pyridines was developed.
Assuntos
Glucagon/antagonistas & inibidores , Piridinas/síntese química , Piridinas/farmacologia , Piridinas/química , Relação Estrutura-AtividadeRESUMO
5-Hydroxyalkyl-4-phenylpyridines have been identified as a novel class of glucagon antagonists with potential utility for the treatment of diabetes. A lead structure with moderate activity was discovered through a high throughput screening assay. Structure-activity relationships led to the discovery of a potent antagonist, IC(50)=0.11 microM, more than 60-fold improvement over the lead structure.