2. Academic Validation
  3. Discovery and optimization of 5-fluoro-4,6-dialkoxypyrimidine GPR119 agonists

Discovery and optimization of 5-fluoro-4,6-dialkoxypyrimidine GPR119 agonists

  • Bioorg Med Chem Lett. 2014 Sep 1;24(17):4332-5. doi: 10.1016/j.bmcl.2014.06.071.
Daniel J Buzard 1,  Sun Hee Kim 2,  Juerg Lehmann 2,  Sangdon Han 2,  Imelda Calderon 2,  Amy Wong 2,  Andrew Kawasaki 2,  Sanju Narayanan 2,  Rohit Bhat 2,  Tawfik Gharbaoui 2,  Luis Lopez 2,  Dawei Yue 2,  Kevin Whelan 2,  Hussien Al-Shamma 2,  David J Unett 2,  Hsin-Hui Shu 2,  Shiu-Feng Tung 2,  Steve Chang 2,  Ching-Fen Chuang 2,  Michael Morgan 2,  Abu Sadeque 2,  Zhi-Liang Chu 2,  James N Leonard 2,  Robert M Jones 2
Affiliations

Affiliations

  • 1 Arena Pharmaceuticals Inc., 6154 Nancy Ridge Drive, San Diego, CA 92121, United States. Electronic address: dbuzard@arenapharm.com.
  • 2 Arena Pharmaceuticals Inc., 6154 Nancy Ridge Drive, San Diego, CA 92121, United States.
PMID: 25088191 DOI: 10.1016/j.bmcl.2014.06.071
Abstract

A series of 5-fluoro-4,6-dialkoxypyrimidine GPR119 modulators were discovered and optimized for in vitro agonist activity. A lead molecule was identified that has improved agonist efficacy relative to our clinical compound (APD597) and possesses reduced CYP2C9 inhibitory potential. This optimized lead was found to be efficacious in rodent models of glucose control both alone and in combination with a Dipeptidyl peptidase-4 (DPP-4) inhibitor.

Keywords

APD597; Diabetes; GDIR; GPR119.

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