title: Optimization of 3-aryl-3-ethoxypropanoic acids and discovery of the potent GPR40 agonist DS-1558.
abstract: GPR40 agonists stimulate insulin secretion only under the presence of high glucose concentration. Based on this mechanism, GPR40 agonists are believed to be promising novel insulin secretagogues with low risk of hypoglycemia. The optimizations of 3-aryl-3-ethoxypropanoic acids were performed to improve in vitro activity. We discovered compound 29r (DS-1558), (3S)-3-ethoxy-3-(4-{[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy}phenyl)propanoic acid, which was confirmed to have an enhancing effect on glucose-dependent insulin secretion after intravenous glucose injection in SD rats.
authors.affiliation: Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address: takano.rieko.u2@daiichisankyo.co.jp.
authors.forename: Rieko
authors.initials: R
authors.lastname: Takano
authors.affiliation: Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Yoshida
authors.affiliation: Venture Science Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Inoue
authors.affiliation: New Modality Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Honda
authors.affiliation: Cardiovascular-Metabolics Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Nakashima
authors.affiliation: Cardiovascular-Metabolics Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Matsumoto
authors.affiliation: Cardiovascular-Metabolics Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Yano
authors.affiliation: Global Project Management Department, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Tsuneaki
authors.initials: T
authors.lastname: Ogata
authors.affiliation: Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Watanabe
authors.affiliation: Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Hirouchi
authors.affiliation: Drug Discovery and Biomedical Technology Unit, Daiichi Sankyo RD Novare Co., Ltd, 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Kimura
authors.affiliation: New Modality Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address: toda.narihiro.jw@daiichisankyo.co.jp.
authors.forename: Narihiro
authors.initials: N
authors.lastname: Toda
mesh_terms: D000818:Animals; D006801:Humans; D007004:Hypoglycemic Agents; D007189:Indans / Q000378:metabolism*; D015394:Molecular Structure; D010666:Phenylpropionates / Q000378:metabolism*; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*
chemical_list: C000595179:3-ethoxy-3-(4-((4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)propanoic acid; C473035:G-protein-coupled receptor 40, rat; D007004:Hypoglycemic Agents; D007189:Indans; D010666:Phenylpropionates; D043562:Receptors, G-Protein-Coupled
keywords: Agonist; DS-1558; GPR40; Glucose-dependent; Insulin secretagogues