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
GPR40 partial agonism is a promising new mechanism for the treatment of type 2 diabetes mellitus with clinical proof of concept. Most of the GPR40 agonists in the literature have a carboxylic acid functional group, which may pose a risk for idiosyncratic drug toxicity. A novel series of GPR40 agonists containing a tetrazole as a carboxylic acid bioisostere was identified. This series of compounds features a benzo[b]thiophene as the center ring, which is prone to oxidation during phase 1 metabolism. Following SAR optimization targeting GPR40 agonist activity and intrinsic clearance in microsomes (human and rat), potent and metabolically stable compounds were selected for in vivo evaluation. The compounds are efficacious at lowering blood glucose in a SD rat oGTT model.
