Minimal Structural Variation of GPR84 Full Agonist Causes Functional Switch to Inverse Agonism

GPR84 is an orphan GPCR that is expressed primarily in immune cells such as neutrophils and macrophages, and that modulates immune responses during inflammation. The receptor has appeared as a promising drug target, and accumulating evidence indicates that GPR84 inhibition is a viable approach for treatment of various inflammatory and fibrotic disorders. Herein, we report the discovery of a minor structural modification resulting in functional switch of agonists to inverse agonists. Subsequent SAR explorations led to the identification of low-nanomolar potency inverse agonists and antagonists, as exemplified by TUG-2181 (40g). Representative compounds exhibited good physicochemical properties, selectivity over other free fatty acid receptors, and the ability to fully inhibit GPR84-mediated neutrophil activation.