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
  • 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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