2. Academic Validation
  3. Discovery of fused bicyclic agonists of the orphan G-protein coupled receptor GPR119 with in vivo activity in rodent models of glucose control

Discovery of fused bicyclic agonists of the orphan G-protein coupled receptor GPR119 with in vivo activity in rodent models of glucose control

  • Bioorg Med Chem Lett. 2011 May 15;21(10):3134-41. doi: 10.1016/j.bmcl.2011.03.007.
Graeme Semple 1,  Albert Ren,  Beatriz Fioravanti,  Guillherme Pereira,  Imelda Calderon,  Karoline Choi,  Yifeng Xiong,  Young-Jun Shin,  Tawfik Gharbaoui,  Carleton R Sage,  Michael Morgan,  Charles Xing,  Zhi-Liang Chu,  James N Leonard,  Andrew J Grottick,  Hussein Al-Shamma,  Yin Liang,  Keith T Demarest,  Robert M Jones
Affiliations

Affiliation

  • 1 Medicinal Chemistry, Arena Pharmaceuticals, 6166 Nancy Ridge Drive, San Diego, CA 92121, USA. gsemple@arenapharm.com
PMID: 21444206 DOI: 10.1016/j.bmcl.2011.03.007
Abstract

We herein outline the design of a new series of agonists of the pancreatic and GI-expressed orphan G-protein coupled receptor GPR119, a target that has been of significant recent interest in the field of metabolism, starting from our prototypical agonist AR231453. A number of key parameters were improved first by incorporation of a pyrazolopyrimidine core to create a new structural series and secondly by the introduction of a piperidine ether group capped with a carbamate. Chronic treatment with one compound from the series, 3k, showed for the first time that blood glucose and glycated hemoglobin (HbA1c) levels could be significantly reduced in Zucker Diabetic Fatty (ZDF) rats over several weeks of dosing. As a result of these and Other data described here, 3k (APD668, JNJ-28630368) was the first compound with this mechanism of action to be progressed into clinical development for the treatment of diabetes.

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