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

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.