ABSTRACT
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.
Subject(s)
Hypoglycemic Agents/chemical synthesis , Piperidines/chemical synthesis , Pyrimidines/chemical synthesis , Pyrroles/chemical synthesis , Receptors, G-Protein-Coupled/agonists , Administration, Oral , Animals , Cell Line , Colon/metabolism , Glucagon-Like Peptide 1/metabolism , Glucose/metabolism , Glucose Tolerance Test , Humans , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/pharmacology , Incretins/metabolism , Intestinal Mucosa/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Piperidines/pharmacokinetics , Piperidines/pharmacology , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Pyrroles/pharmacokinetics , Pyrroles/pharmacology , Rats , Rats, Sprague-Dawley , Rats, Wistar , Stereoisomerism , Structure-Activity RelationshipABSTRACT
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.
