Loukas Ieremias, Asmita Manandhar, Katrine Schultz-Knudsen, Mads Holmgaard Kaspersen, Christina Ioanna Vrettou, Elisabeth Rexen Ulven and Trond Ulven*,
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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.
期刊介绍：
The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents.
The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.
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