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
We report the synthesis and biological activity of a series of 2-cyano-4-fluoro-1-thiovalylpyrrolidine inhibitors of DPP-IV. Within this series, compound 19 provided a potent, selective, and orally active DPP-IV inhibitor which demonstrated a very long duration of action in both rat and dog.