Optimization of 3-aryl-3-ethoxypropanoic acids and discovery of the potent GPR40 agonist DS-1558. Issue 17 (1st September 2015)

• Record Type: Journal Article
• Authors: Takano, Rieko; Yoshida, Masao; Inoue, Masahiro; Honda, Takeshi; Nakashima, Ryutaro; Matsumoto, Koji; Yano, Tatsuya; Ogata, Tsuneaki; Watanabe, Nobuaki; Hirouchi, Masakazu; Kimura, Takako; Toda, Narihiro
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 17(2015)
• Page Start: 5546
• Page End: 5565
• Publication Date: 2015-09-01
• Subjects: GPR40 -- Agonist -- Glucose-dependent -- Insulin secretagogues -- DS-1558; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.07.028
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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 compound29r (DS-1558), (3 S )-3-ethoxy-3-(4-{[(1 R )-4-(trifluoromethyl)-2, 3-dihydro-1 H -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.