Discovery of 3-aryl-3-ethoxypropanoic acids as orally active GPR40 agonists

  • Bioorg Med Chem Lett. 2014 Jul 1;24(13):2949-53. doi: 10.1016/j.bmcl.2014.04.065.
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 ,  Narihiro Toda  2
Affiliations
  • 1. R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • 2. R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address: [email protected].
PMID: 24835985 DOI: 10.1016/j.bmcl.2014.04.065
Abstract

The G protein-coupled receptor 40 (GPR40) mediates enhancement of glucose-stimulated Insulin secretion in pancreatic β cells. The GPR40 agonist has been attracting attention as a novel Insulin secretagogue with glucose dependency for the treatment of type 2 diabetes. The optimization study of compound 1 led to a potent and bioavailable GPR40 agonist 24, which showed Insulin secretion and glucose lowering effects in rat OGTT. Compound 24 is a potential lead compound for a novel Insulin secretagogue with a low risk of hypoglycemia.

Keywords
Agonist; Diabetes; GPR40; Glucose lowering; Insulin secretagogue.