Synthesis and evaluation of 3-(4-(phenoxymethyl)phenyl)propanoic acid and N-phenylbenzenesulfonamide derivatives as FFA4 agonists

Bioorg Med Chem Lett. 2020 Dec 15;30(24):127650. doi: 10.1016/j.bmcl.2020.127650. Epub 2020 Oct 28.

Abstract

Free fatty acid receptor 4 (FFA4) has been recognized as an attractive target in metabolic diseases. To find potent and selective FFA4 agonist, 28 compounds of 3-(4-(phenoxymethyl)phenyl)propanoic acid and N-phenylbenzenesulfonamide derivatives were designed and synthesized, featuring OC and SO2-N linkage. For the OC linkage compounds, 1g showed the most potent FFA4 agonistic activity with a pEC50 of 5.81 ± 0.04 and exhibited at least 64-fold selectivity against FFA1. For SO2-N linkage agonists, 2m had a pEC50 of 5.66 ± 0.04 and displayed>46-fold selectivity against FFA1. Among these two series of compounds, 1g was the most potent agonist at FFA4 and the best selectivity against FFA1, demonstrated by docking simulation. Moreover, 1g showed receptor selectivity on other seven GPCRs. In anti-diabetic evaluation, 1g dose-dependently reduced blood glucose, which was better than a clinical phase III drug TAK875. This study provides guidance for FFA4 ligand design and drug optimization.

Keywords: Agonist; Dynamic mass redistribution; Free fatty acid receptor 4; GPR120; Type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Molecular Docking Simulation
  • Propionates / chemical synthesis
  • Propionates / chemistry*
  • Propionates / pharmacology*
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / metabolism
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry*
  • Sulfonamides / pharmacology*

Substances

  • FFAR4 protein, human
  • Propionates
  • Receptors, G-Protein-Coupled
  • Sulfonamides