RESUMEN
GPR119 is a 7-transmembrane receptor that is expressed in the enteroendocrine cells in the intestine and in the islets of Langerhans in the pancreas. Indolines and 6,7-dihydro-5H-pyrrolo[2,3-a]pyrimidines were discovered as G protein-coupled receptor 119 (GPR119) agonists, and lead optimization efforts led to the identification of 1-methylethyl 4-({7-[2-fluoro-4-(methylsulfonyl)phenyl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}oxy)-1-piperidinecarboxylate (GSK1104252A) (3), a potent and selective GPR119 agonist. Compound 3 showed excellent pharmacokinetic properties and sufficient selectivity with in vivo studies supporting a role for GPR119 in glucose homeostasis in the rodent. Thus, 3 appeared to modulate the enteroinsular axis, improve glycemic control, and strengthen previous suggestions that GPR119 agonists may have utility in the treatment of type 2 diabetes.
Asunto(s)
Hipoglucemiantes/síntesis química , Piperidinas/síntesis química , Pirimidinas/síntesis química , Pirroles/síntesis química , Receptores Acoplados a Proteínas G/agonistas , Administración Oral , Animales , Línea Celular , Colon/metabolismo , Péptido 1 Similar al Glucagón/metabolismo , Glucosa/metabolismo , Prueba de Tolerancia a la Glucosa , Humanos , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Incretinas/metabolismo , Mucosa Intestinal/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Piperidinas/farmacocinética , Piperidinas/farmacología , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Pirroles/farmacocinética , Pirroles/farmacología , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Dipeptidyl peptidase-IV (DPP-IV) regulates metabolism by degrading incretins involved in nutritional regulation. Metformin and pioglitazone improve insulin sensitivity whereas glyburide promotes insulin secretion. Zucker diabetic rats were treated with these antidiabetic agents for 2 weeks and DPP-IV activity and expression were determined. Serum DPP-IV activity increased whereas tissue activity decreased as the rats aged. Treatment of rats with metformin, pioglitazone, and glyburide did not alter DPP-IV mRNA expression in liver or kidney. Metformin and pioglitazone significantly (P<0.05) reduced serum DPP-IV activity and glycosylated hemoglobin. Glyburide did not lower DPP-IV activity or glycosylated hemoglobin. Regression analysis showed serum DPP-IV activity correlated with glycosylated hemoglobin (r=0.92) and glucagon-like peptide-1 levels (r=-0.49). Metformin, pioglitazone, and glyburide had no effect on serum DPP-IV activity in vitro, indicating these are not competitive DPP-IV inhibitors. We propose the in vivo inhibitory effects observed with metformin and pioglitazone on serum DPP-IV activity results from reduced DPP-IV secretion.