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

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

  • J Med Chem. 2012 Dec 27;55(24):10972-94. doi: 10.1021/jm301404a.
Subba R Katamreddy 1,  Andrew J Carpenter,  Carina E Ammala,  Eric E Boros,  Ron L Brashear,  Celia P Briscoe,  Sarah R Bullard,  Richard D Caldwell,  Christopher R Conlee,  Dallas K Croom,  Shane M Hart,  Dennis O Heyer,  Paul R Johnson,  Jennifer A Kashatus,  Doug J Minick,  Gregory E Peckham,  Sean A Ross,  Shane G Roller,  Vicente A Samano,  Howard R Sauls,  Sarva M Tadepalli,  James B Thompson,  Yun Xu,  James M Way
Affiliations

Affiliation

  • 1 GlaxoSmithKline Research & Development, Five Moore Drive, Research Triangle Park, North Carolina 27709, USA. [email protected]
PMID: 23214471 DOI: 10.1021/jm301404a
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.

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