2. Academic Validation
  3. Investigating the Structure-Activity Relationship of 1,2,4-Triazine G-Protein-Coupled Receptor 84 (GPR84) Antagonists

Investigating the Structure-Activity Relationship of 1,2,4-Triazine G-Protein-Coupled Receptor 84 (GPR84) Antagonists

  • J Med Chem. 2022 Aug 25;65(16):11270-11290. doi: 10.1021/acs.jmedchem.2c00804.
Amit Mahindra 1,  Laura Jenkins 2,  Sara Marsango 2,  Mark Huggett 3 4,  Margaret Huggett 3 4,  Lindsay Robinson 3 4,  Jonathan Gillespie 3 4,  Muralikrishnan Rajamanickam 3 4,  Angus Morrison 3 4,  Stuart McElroy 3 4,  Irina G Tikhonova 5,  Graeme Milligan 2,  Andrew G Jamieson 1
Affiliations

Affiliations

  • 1 School of Chemistry, University of Glasgow, Joseph Black Building, University Avenue, Glasgow G12 8QQ, U.K.
  • 2 Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, University of Glasgow, Davidson Building, Glasgow G12 8QQ, U.K.
  • 3 BioAscent Discovery Ltd., Newhouse, Lanarkshire ML1 5UH, U.K.
  • 4 European Screening Centre, University of Dundee, Newhouse, Lanarkshire ML1 5UH, U.K.
  • 5 School of Pharmacy, Medical Biology Centre, Queen's University Belfast, Belfast BT9 7BL, U.K.
PMID: 35948061 DOI: 10.1021/acs.jmedchem.2c00804
Abstract

G-protein-coupled receptor 84 (GPR84) is a proinflammatory orphan G-protein-coupled receptor implicated in several inflammatory and fibrotic diseases. Several agonist and antagonist ligands have been developed that target GPR84; however, a noncompetitive receptor blocker that was progressed to phase II clinical trials failed to demonstrate efficacy. New high-quality antagonists are required to investigate the pathophysiological role of GPR84 and to validate GPR84 as a therapeutic target. We previously reported the discovery of a novel triazine GPR84 competitive antagonist 1. Here, we describe an extensive structure-activity relationship (SAR) of antagonist 1 and also present in silico docking with supporting mutagenesis studies that reveals a potential binding pose for this type of orthosteric antagonist. Lead compound 42 is a potent GPR84 antagonist with a favorable pharmacokinetic (PK) profile suitable for further drug development.

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