Development of Highly Potent, G-Protein Pathway Biased, Selective, and Orally Bioavailable GPR84 Agonists

  • J Med Chem. 2024 Jan 11;67(1):110-137. doi: 10.1021/acs.jmedchem.3c00951.
Pinqi Wang  1  2 ,  Arun Raja  1  2 ,  Vincent B Luscombe  3 ,  Carole J R Bataille  1  2 ,  Daniel Lucy  1  3 ,  Vanessa V Rogga  1 ,  David R Greaves  3 ,  Angela J Russell  1  2
Affiliations
  • 1. Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
  • 2. Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, U.K.
  • 3. Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, U.K.
PMID: 38146625 DOI: 10.1021/acs.jmedchem.3c00951
Abstract

Orphan G-protein-coupled receptor 84 (GPR84) is a receptor that has been linked to Cancer, inflammatory, and fibrotic diseases. We have reported DL-175 as a biased agonist at GPR84 which showed differential signaling via Gαi/cAMP and β-arrestin, but which is rapidly metabolized. Herein, we describe an optimization of DL-175 through a systematic structure-activity relationship (SAR) analysis. This reveals that the replacement of the naphthalene group improved metabolic stability and the addition of a 5-hydroxy substituent to the pyridine N-oxide group, yielding compounds 68 (OX04528) and 69 (OX04529), enhanced the potency for cAMP signaling by 3 orders of magnitude to low picomolar values. Neither compound showed detectable effects on β-arrestin recruitment up to 80 μM. Thus, the new GPR84 agonists 68 and 69 displayed excellent potency, high G-protein signaling bias, and an appropriate in vivo pharmacokinetic profile that will allow investigation of GPR84 biased agonist activity in vivo.

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