Discovery of novel benzo[b]thiophene tetrazoles as non-carboxylate GPR40 agonists. Issue 3 (1st February 2018)

• Record Type: Journal Article
• Authors: Huang, Hui; Winters, Michael P.; Meegalla, Sanath K.; Arnoult, Eric; Paul Lee, S.; Zhao, Shuyuan; Martin, Tonya; Rady, Brian; Liu, Jianying; Towers, Meghan; Otieno, Monicah; Xu, Fran; Lim, Heng Keang; Silva, Jose; Pocai, Alessandro; Player, Mark R.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 28:Issue 3(2018)
• Page Start: 429
• Page End: 436
• Publication Date: 2018-02-01
• Subjects: GPR40 agonist -- Tetrazole -- Type 2 diabetes -- GPCR -- GSIS; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2017.12.022
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: GPR40 partial agonism is a promising new mechanism for the treatment of type 2 diabetes mellitus with clinical proof of concept. Most of the GPR40 agonists in the literature have a carboxylic acid functional group, which may pose a risk for idiosyncratic drug toxicity. A novel series of GPR40 agonists containing a tetrazole as a carboxylic acid bioisostere was identified. This series of compounds features a benzo[ b ]thiophene as the center ring, which is prone to oxidation during phase 1 metabolism. Following SAR optimization targeting GPR40 agonist activity and intrinsic clearance in microsomes (human and rat), potent and metabolically stable compounds were selected for in vivo evaluation. The compounds are efficacious at lowering blood glucose in a SD rat oGTT model.