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, 42E2 (pA2 = 8.41, pKi =
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.