Discovery of novel benzo[b]thiophene tetrazoles as non-carboxylate GPR40 agonists.

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.

• Authors: Hui Huang, Michael P Winters, Sanath K Meegalla, Eric Arnoult, S Paul Lee, Shuyuan Zhao, Tonya Martin, Brian Rady, Jianying Liu, Meghan Towers, Monicah Otieno, Fran Xu, Heng Keang Lim, Jose Silva, Alessandro Pocai, Mark R Player
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 28 Issue 3 Pg. 429-436 (02 01 2018) ISSN: 1464-3405 [Electronic] England
• PMID: 29258772 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier Ltd. All rights reserved.

Chemical References

• FFAR1 protein, human
• G-protein-coupled receptor 40, rat
• Receptors, G-Protein-Coupled
• Tetrazoles
• Thiophenes
• benzothiophene

Topics

• Animals
• Dogs
• Dose-Response Relationship, Drug
• Drug Discovery
• Humans
• Models, Molecular
• Molecular Structure
• Rats
• Receptors, G-Protein-Coupled (agonists)
• Structure-Activity Relationship
• Tetrazoles (chemical synthesis, chemistry, pharmacology)
• Thiophenes (chemistry, pharmacology)