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Discovery of DS-1558: A Potent and Orally Bioavailable GPR40 Agonist.

ABSTRACT: GPR40 is a G protein-coupled receptor that is predominantly expressed in pancreatic β-cells. GPR40 agonists stimulate insulin secretion in the presence of high glucose concentration. On the basis of this mechanism, GPR40 agonists are possible novel insulin secretagogues with reduced or no risk of hypoglycemia. The improvement of in vitro activity and metabolic stability of compound 1 led to the discovery of 13, (3S)-3-ethoxy-3-(4-{[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy}phenyl)propanoic acid, as a potent and orally available GPR40 agonist. Compound 13 (DS-1558) was found to have potent glucose lowering effects during an oral glucose tolerance test in ZDF rats.

SUBMITTER: Takano R

PROVIDER: S-EPMC4360146 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Discovery of DS-1558: A Potent and Orally Bioavailable GPR40 Agonist.

Takano Rieko R Yoshida Masao M Inoue Masahiro M Honda Takeshi T Nakashima Ryutaro R Matsumoto Koji K Yano Tatsuya T Ogata Tsuneaki T Watanabe Nobuaki N Hirouchi Masakazu M Yoneyama Tomoko T Ito Shuichiro S Toda Narihiro N

ACS medicinal chemistry letters 20150113 3

GPR40 is a G protein-coupled receptor that is predominantly expressed in pancreatic β-cells. GPR40 agonists stimulate insulin secretion in the presence of high glucose concentration. On the basis of this mechanism, GPR40 agonists are possible novel insulin secretagogues with reduced or no risk of hypoglycemia. The improvement of in vitro activity and metabolic stability of compound 1 led to the discovery of 13, (3S)-3-ethoxy-3-(4-{[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy}phenyl)pr ...[more]

PMID: 25815144

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