2. Academic Validation
  3. Optimization of 3-aryl-3-ethoxypropanoic acids and discovery of the potent GPR40 agonist DS-1558

Optimization of 3-aryl-3-ethoxypropanoic acids and discovery of the potent GPR40 agonist DS-1558

  • Bioorg Med Chem. 2015 Sep 1;23(17):5546-65. doi: 10.1016/j.bmc.2015.07.028.
Rieko Takano 1,  Masao Yoshida 2,  Masahiro Inoue 3,  Takeshi Honda 4,  Ryutaro Nakashima 5,  Koji Matsumoto 5,  Tatsuya Yano 5,  Tsuneaki Ogata 6,  Nobuaki Watanabe 7,  Masakazu Hirouchi 7,  Takako Kimura 8,  Narihiro Toda 9
Affiliations

Affiliations

  • 1 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.
  • 2 Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • 3 Venture Science Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • 4 New Modality Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • 5 Cardiovascular-Metabolics Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • 6 Global Project Management Department, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • 7 Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • 8 Drug Discovery and Biomedical Technology Unit, Daiichi Sankyo RD Novare Co., Ltd, 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
  • 9 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.
PMID: 26234904 DOI: 10.1016/j.bmc.2015.07.028
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.

Keywords

Agonist; DS-1558; GPR40; Glucose-dependent; Insulin secretagogues.

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