RESUMO
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.
Assuntos
Hipoglicemiantes/síntese química , Piperidinas/síntese química , Pirimidinas/síntese química , Pirróis/síntese química , Receptores Acoplados a Proteínas G/agonistas , Administração Oral , Animais , Linhagem Celular , Colo/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Glucose/metabolismo , Teste de Tolerância a Glucose , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Incretinas/metabolismo , Mucosa Intestinal/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Piperidinas/farmacocinética , Piperidinas/farmacologia , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Pirróis/farmacocinética , Pirróis/farmacologia , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Traditional approaches to discovery of selective estrogen receptor modulators (SERMs) have relied on ER binding and cell-based estrogen response element-driven assays to identify compounds that are osteoprotective but nonproliferative in breast and uterine tissues. To discover new classes of potential SERMs, we have employed a cell-free microsphere-based binding assay to rapidly characterize ERalpha interactions with conformation-sensing cofactor or phage display peptides. Peptide profiles of constrained triarenes were compared to known proliferative and nonproliferative ER ligands to discover potent quinoline-based ligands with minimal Ishikawa cell stimulation.