Discovery of 6,7-dihydro-5H-pyrrolo[2,3-a]pyrimidines as orally available G protein-coupled receptor 119 agonists.

Basic Information

ID: ALA2176966

Journal: J Med Chem

Title: Discovery of 6,7-dihydro-5H-pyrrolo[2,3-a]pyrimidines as orally available G protein-coupled receptor 119 agonists.

Authors: Katamreddy SR, Carpenter AJ, Ammala CE, Boros EE, Brashear RL, Briscoe CP, Bullard SR, Caldwell RD, Conlee CR, Croom DK, Hart SM, Heyer DO, Johnson PR, Kashatus JA, Minick DJ, Peckham GE, Ross SA, Roller SG, Samano VA, Sauls HR, Tadepalli SM, Thompson JB, Xu Y, Way JM.

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.

CiteXplore: 23214471

DOI: 10.1021/jm301404a

Patent ID: