Discovery, Structure–Activity Relationship, and Functional Characterization of a Chromenopyrrole Series as Orthosteric Antagonists of GPR84

GPR84 is a proinflammatory G-protein-coupled receptor implicated in autoimmune and fibrotic disorders. Although orthosteric antagonists have been reported, their physicochemical limitations have hindered development. Here, we describe the discovery and optimization of a chromenopyrrole scaffold as a new class of orthosteric GPR84 antagonists. Guided by molecular modeling and iterative SAR, we identified ligands that competitively inhibit agonist binding, confirmed by Schild analysis and radioligand displacement. Structural refinement defined key steric and hydrophobic features required for high-affinity binding, culminating in the isolation of a single active enantiomer, <b>42E2</b> (p<i>A</i>₂ = 8.41, p<i>K</i>_i = 8.16). This chemotype displays improved drug-like properties relative to earlier series and strong selectivity over related free fatty acid receptors. Preliminary pharmacokinetic studies indicate favorable solubility and plasma protein binding, although metabolic stability remains to be optimized. These results expand the chemical space for GPR84 modulation and provide a foundation for therapeutic development and mechanistic investigation.