Structure-Activity Relationship Explorations and Discovery of a Potent Antagonist for the Free Fatty Acid Receptor 2

ChemMedChem. 2021 Nov 5;16(21):3326-3341. doi: 10.1002/cmdc.202100356. Epub 2021 Sep 12.

Abstract

Free fatty acid receptor 2 (FFA2) is a sensor for short-chain fatty acids that has been identified as an interesting potential drug target for treatment of metabolic and inflammatory diseases. Although several ligand series are known for the receptor, there is still a need for improved compounds. One of the most potent and frequently used antagonists is the amide-substituted phenylbutanoic acid known as CATPB (1). We here report the structure-activity relationship exploration of this compound, leading to the identification of homologues with increased potency. The preferred compound 37 (TUG-1958) was found, besides improved potency, to have high solubility and favorable pharmacokinetic properties.

Keywords: FFA2; GPCR; GPR43; inflammation; short-chain fatty acids.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemical synthesis
  • Amides / chemistry
  • Amides / pharmacology*
  • Animals
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Mice
  • Molecular Structure
  • Phenylbutyrates / chemical synthesis
  • Phenylbutyrates / chemistry
  • Phenylbutyrates / pharmacology*
  • Receptors, Cell Surface / antagonists & inhibitors*
  • Receptors, Cell Surface / metabolism
  • Structure-Activity Relationship

Substances

  • Amides
  • FFA2R protein, human
  • Phenylbutyrates
  • Receptors, Cell Surface
  • free fatty acid 2 receptor, mouse