RESUMEN
Compound 12 is a GPR40 agonist that realizes the full magnitude of efficacy possible via GPR40 receptor agonism. In vitro and in vivo studies demonstrated superior glucose lowering by 12 compared to fasiglifam (TAK-875), in a glucose dependent manner. The enhanced efficacy observed with the full agonist 12 was associated with both direct and indirect stimulation of insulin secretion.
Asunto(s)
Hipoglucemiantes/farmacología , Pirazinas/farmacología , Receptores Acoplados a Proteínas G/agonistas , Animales , Benzofuranos/farmacología , Compuestos de Bifenilo/farmacología , Células CHO , Cricetulus , Perros , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Glucurónidos/biosíntesis , Humanos , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Hipoglucemiantes/metabolismo , Macaca fascicularis , Ratones , Microsomas Hepáticos/metabolismo , Simulación del Acoplamiento Molecular , Estructura Molecular , Fenilpropionatos/farmacología , Piperidinas/farmacología , Pirazinas/síntesis química , Pirazinas/química , Pirazinas/metabolismo , Pirimidinas/farmacología , Ratas , Relación Estructura-Actividad , Sulfonas/farmacologíaRESUMEN
High-throughput screening of a subset of the J&J compound library containing the carboxylic acid functional group uncovered a bromophenyl derivative as a moderate potent GPR40 agonist. Chemical elaboration of this bromophenyl led to the discovery of a novel series of GPR40 agonists with submicromolar potency. Among them, 22 and 24 behaved as full agonists when compared to the endogenous GPR40 ligand linolenic acid in a functional Ca+2 flux assay in HEK cells expressing GPR40 receptor. Several GPR40 agonists have also demonstrated the ability to induce glucose-mediated insulin secretion in the mouse MIN6 pancreatic beta-cell line. Our data supports the hypothesis that GPR40 may play an important role in fatty acid-mediated glucose-dependent insulin secretion. Compound 22 exhibited good pharmacokinetic profile in rat and may serve as a good candidate for in vivo study and may help to determine if GPR40 agonists would be beneficial in the treatment of type II diabetes.