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Discovery of TAK-875: A Potent, Selective, and Orally Bioavailable GPR40 Agonist

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posted on 2010-09-09, 00:00 authored by Nobuyuki Negoro, Shinobu Sasaki, Satoshi Mikami, Masahiro Ito, Masami Suzuki, Yoshiyuki Tsujihata, Ryo Ito, Ayako Harada, Koji Takeuchi, Nobuhiro Suzuki, Junichi Miyazaki, Takashi Santou, Tomoyuki Odani, Naoyuki Kanzaki, Miyuki Funami, Toshimasa Tanaka, Akifumi Kogame, Shinichiro Matsunaga, Tsuneo Yasuma, Yu Momose
GPR40, one of the G protein-coupled receptors predominantly expressed in pancreatic β-cells, mediates enhancement of glucose-stimulated insulin secretion by free fatty acids. A potent and selective GPR40 agonist is theorized to be a safe and effective antidiabetic drug with little or no risk of hypoglycemia. Cyclization of the phenylpropanoic acid moiety of lead compound 1 produced fused phenylalkanoic acids with favorable in vitro agonist activities and pharmacokinetic profiles. Further optimization led to the discovery of dihydrobenzofuran derivative 9a ([(3S)-6-({2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid hemi-hydrate, TAK-875) as a potent, selective, and orally bioavailable GPR40 agonist, with a pharmacokinetic profile enabling long-acting drug efficacy. Compound 9a showed potent plasma glucose-lowering action and insulinotropic action during an oral glucose tolerance test in female Wistar fatty rats with impaired glucose tolerance. Compound 9a is currently in clinical trials for the treatment of type 2 diabetes mellitus.

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