Discovery of Potent Tetrazole Free Fatty Acid Receptor 2 Antagonists

  • J Med Chem. 2023 May 11;66(9):6105-6121. doi: 10.1021/acs.jmedchem.2c01935.
Alice Valentini  1 ,  Katrine Schultz-Knudsen  1 ,  Anders Højgaard Hansen  2 ,  Argyro Tsakoumagkou  1 ,  Laura Jenkins  3 ,  Henriette B Christensen  2 ,  Asmita Manandhar  1 ,  Graeme Milligan  3 ,  Trond Ulven  1  2 ,  Elisabeth Rexen Ulven  1
Affiliations
  • 1. Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
  • 2. Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark.
  • 3. Centre for Translational Pharmacology, School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland, United Kingdom.
PMID: 37129317 DOI: 10.1021/acs.jmedchem.2c01935
Abstract

The Free Fatty Acid Receptor 2 (FFA2), also known as GPR43, mediates effects of short-chain fatty acids and has attracted interest as a potential target for treatment of various metabolic and inflammatory diseases. Herein, we report the results from bioisosteric replacement of the carboxylic acid group of the established FFA2 antagonist CATPB and SAR investigations around these compounds, leading to the discovery of the first high-potency FFA2 antagonists, with the preferred compound TUG-2304 (16l) featuring IC50 values of 3-4 nM in both cAMP and GTPγS assays, favorable physicochemical and pharmacokinetic properties, and the ability to completely inhibit propionate-induced neutrophil migration and respiratory burst.

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