title: Discovery of DS-1558: A Potent and Orally Bioavailable GPR40 Agonist.
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.
authors: R&D Division, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors: Rieko
authors: R
authors: Takano
authors: R&D Division, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors: Masao
authors: M
authors: Yoshida
authors: R&D Division, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors: Masahiro
authors: M
authors: Inoue
authors: R&D Division, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors: Takeshi
authors: T
authors: Honda
authors: R&D Division, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors: Ryutaro
authors: R
authors: Nakashima
authors: R&D Division, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors: Koji
authors: K
authors: Matsumoto
authors: R&D Division, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors: Tatsuya
authors: T
authors: Yano
authors: R&D Division, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors: Tsuneaki
authors: T
authors: Ogata
authors: R&D Division, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors: Nobuaki
authors: N
authors: Watanabe
authors: R&D Division, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors: Masakazu
authors: M
authors: Hirouchi
authors: Drug Discovery and Biomedical Technology Unit, Daiichi Sankyo RD Novare Co., Ltd. , 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
authors: Tomoko
authors: T
authors: Yoneyama
authors: Drug Discovery and Biomedical Technology Unit, Daiichi Sankyo RD Novare Co., Ltd. , 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
authors: Shuichiro
authors: S
authors: Ito
authors: R&D Division, Daiichi Sankyo Co., Ltd. , 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors: Narihiro
authors: N
authors: Toda
keywords: GPR40; agonist; diabetes; glucose lowering; insulin secretagogue