title: Discovery of TAK-875: A Potent, Selective, and Orally Bioavailable GPR40 Agonist.
abstract: 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.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Negoro
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan.
authors.forename: Shinobu
authors.initials: S
authors.lastname: Sasaki
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Mikami
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ito
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Tsujihata
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Ito
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Harada
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Takeuchi
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Suzuki
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Miyazaki
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Santou
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Odani
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kanzaki
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Funami
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan.
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan.
authors.forename: Akifumi
authors.initials: A
authors.lastname: Kogame
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Matsunaga
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan.
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Yasuma
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Momose
keywords: GPR40; GSIS; OGTT; TAK-875; agonist; insulin secretagogue