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Optimization of 3-aryl-3-ethoxypropanoic acids and discovery of the potent GPR40 agonist DS-1558.
Takano, Rieko; Yoshida, Masao; Inoue, Masahiro; Honda, Takeshi; Nakashima, Ryutaro; Matsumoto, Koji; Yano, Tatsuya; Ogata, Tsuneaki; Watanabe, Nobuaki; Hirouchi, Masakazu; Kimura, Takako; Toda, Narihiro.
Affiliation
  • Takano R; 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.
  • Yoshida M; Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • Inoue M; Venture Science Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • Honda T; New Modality Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • Nakashima R; Cardiovascular-Metabolics Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • Matsumoto K; Cardiovascular-Metabolics Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • Yano T; Cardiovascular-Metabolics Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • Ogata T; Global Project Management Department, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • Watanabe N; Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • Hirouchi M; Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • Kimura T; Drug Discovery and Biomedical Technology Unit, Daiichi Sankyo RD Novare Co., Ltd, 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
  • Toda N; 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.
Bioorg Med Chem ; 23(17): 5546-65, 2015 Sep 01.
Article in En | MEDLINE | ID: mdl-26234904
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.
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Full text: 1 Database: MEDLINE Main subject: Phenylpropionates / Receptors, G-Protein-Coupled / Indans Limits: Animals / Humans Language: En Journal: Bioorg Med Chem Journal subject: BIOQUIMICA / QUIMICA Year: 2015 Type: Article
Fulltext
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Full text: 1 Database: MEDLINE Main subject: Phenylpropionates / Receptors, G-Protein-Coupled / Indans Limits: Animals / Humans Language: En Journal: Bioorg Med Chem Journal subject: BIOQUIMICA / QUIMICA Year: 2015 Type: Article