Discovery of 3-aryl-3-ethoxypropanoic acids as orally active GPR40 agonists.
The G protein-coupled receptor 40 (GPR40) mediates enhancement of glucose-stimulated insulin secretion in pancreatic β cells. The GPR40 agonist has been attracting attention as a novel insulin secretagogue with glucose dependency for the treatment of type 2 diabetes. The optimization study of compound 1 led to a potent and bioavailable GPR40 agonist 24, which showed insulin secretion and glucose lowering effects in rat OGTT. Compound 24 is a potential lead compound for a novel insulin secretagogue with a low risk of hypoglycemia.
R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
Rieko
R
Takano
R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
Masao
M
Yoshida
R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
Masahiro
M
Inoue
R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
Takeshi
T
Honda
R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
Ryutaro
R
Nakashima
R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
Koji
K
Matsumoto
R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
Tatsuya
T
Yano
R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
Tsuneaki
T
Ogata
R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
Nobuaki
N
Watanabe
R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address: toda.narihiro.jw@daiichisankyo.co.jp.
Narihiro
N
Toda
D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D005951:Glucose Tolerance Test; D006801:Humans; D015394:Molecular Structure; D011422:Propionates / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D011924:Rats, Zucker; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013329:Structure-Activity Relationship
D001786:Blood Glucose; C473034:FFAR1 protein, human; C473035:G-protein-coupled receptor 40, rat; D011422:Propionates; D043562:Receptors, G-Protein-Coupled; C029658:propionic acid
Agonist; Diabetes; GPR40; Glucose lowering; Insulin secretagogue