Discovery of a second generation agonist of the orphan G-protein coupled receptor GPR119 with an improved profile

  • Bioorg Med Chem Lett. 2012 Feb 15;22(4):1750-5. doi: 10.1016/j.bmcl.2011.12.092.
Graeme Semple  1 ,  Juerg Lehmann ,  Amy Wong ,  Albert Ren ,  Marc Bruce ,  Young-Jun Shin ,  Carleton R Sage ,  Michael Morgan ,  Wei-Chao Chen ,  Kristen Sebring ,  Zhi-Liang Chu ,  James N Leonard ,  Hussein Al-Shamma ,  Andrew J Grottick ,  Fuyong Du ,  Yin Liang ,  Keith Demarest ,  Robert M Jones
Affiliations
  • 1. Medicinal Chemistry, Arena Pharmaceuticals, San Diego, CA 92121, USA. [email protected]
PMID: 22264481 DOI: 10.1016/j.bmcl.2011.12.092
Abstract

The design and synthesis of a second generation GPR119-agonist clinical candidate for the treatment of diabetes is described. Compound 16 (APD597, JNJ-38431055) was selected for preclinical development based on a good balance between agonist potency, intrinsic activity and in particular on its good solubility and reduced drug-drug interaction potential. In addition, extensive in vivo studies showed a more favorable metabolic profile that may avoid the generation of long lasting metabolites with the potential to accumulate in clinical studies.

Products