Discovery of DS-1558: A Potent and Orally Bioavailable GPR40 Agonist

  • ACS Med Chem Lett. 2015 Jan 13;6(3):266-70. doi: 10.1021/ml500391n.
Rieko Takano  1 ,  Masao Yoshida  1 ,  Masahiro Inoue  1 ,  Takeshi Honda  1 ,  Ryutaro Nakashima  1 ,  Koji Matsumoto  1 ,  Tatsuya Yano  1 ,  Tsuneaki Ogata  1 ,  Nobuaki Watanabe  1 ,  Masakazu Hirouchi  1 ,  Tomoko Yoneyama  2 ,  Shuichiro Ito  2 ,  Narihiro Toda  1
Affiliations
  • 1. R&D Division, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • 2. Drug Discovery and Biomedical Technology Unit, Daiichi Sankyo RD Novare Co., Ltd. , 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
PMID: 25815144 DOI: 10.1021/ml500391n
Abstract

GPR40 is a G protein-coupled receptor that is predominantly expressed in pancreatic β-cells. GPR40 agonists stimulate Insulin secretion in the presence of high glucose concentration. On the basis of this mechanism, GPR40 agonists are possible novel Insulin secretagogues with reduced or no risk of hypoglycemia. The improvement of in vitro activity and metabolic stability of compound 1 led to the discovery of 13, (3S)-3-ethoxy-3-(4-{[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy}phenyl)propanoic acid, as a potent and orally available GPR40 agonist. Compound 13 (DS-1558) was found to have potent glucose lowering effects during an oral glucose tolerance test in ZDF rats.

Keywords
GPR40; agonist; diabetes; glucose lowering; insulin secretagogue.