Discovery of 6,7-Dihydro-5H-pyrrolo[2,3-a]pyrimidines as Orally Available G Protein-Coupled Receptor 119 Agonists
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- 作者：Subba R. Katamreddy ; 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
- 刊名：Journal of Medicinal Chemistry
- 出版年：2012
- 出版时间：December 27, 2012
- 年：2012
- 卷：55
- 期：24
- 页码：10972-10994
- 全文大小：786K
- 年卷期：v.55,no.24(December 27, 2012)
- ISSN：1520-4804
文摘
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.