Minimal Structural Variation of GPR84 Full Agonist Causes Functional Switch to Inverse Agonism

  • J Med Chem. 2025 Apr 24;68(8):7973-8009. doi: 10.1021/acs.jmedchem.4c02335.
Loukas Ieremias  1 ,  Asmita Manandhar  1 ,  Katrine Schultz-Knudsen  1 ,  Mads Holmgaard Kaspersen  1  2 ,  Christina Ioanna Vrettou  1 ,  Elisabeth Rexen Ulven  1 ,  Trond Ulven  1  2
Affiliations
  • 1. Department of Drug Design and Pharmacology, Faculty of Health, University of Copenhagen, 2100 Copenhagen Ø, Denmark.
  • 2. Department of Physics, Chemistry and Pharmacy, Faculty of Science, University of Southern Denmark, 5230 Odense M, Denmark.
PMID: 40183744 DOI: 10.1021/acs.jmedchem.4c02335
Abstract

GPR84 is an orphan GPCR that is expressed primarily in immune cells such as neutrophils and macrophages, and that modulates immune responses during inflammation. The receptor has appeared as a promising drug target, and accumulating evidence indicates that GPR84 inhibition is a viable approach for treatment of various inflammatory and fibrotic disorders. Herein, we report the discovery of a minor structural modification resulting in functional switch of agonists to inverse agonists. Subsequent SAR explorations led to the identification of low-nanomolar potency inverse agonists and antagonists, as exemplified by TUG-2181 (40g). Representative compounds exhibited good physicochemical properties, selectivity over Other free fatty acid receptors, and the ability to fully inhibit GPR84-mediated neutrophil activation.

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