Neutrophils play a central role in the initiation of inflammation. Dysregulated neutrophils produce excessive inflammatory mediators, contributing to the development and progression of autoimmune and inflammatory diseases. Formyl peptide receptor 1 (FPR1) is a G protein-coupled receptor that plays a key role in regulating neutrophil activation and is a promising target for therapeutic intervention. In this study, we used structure-based virtual screening to identify potential FPR1 inhibitors. We initially identified compound 333728 as a hit FPR1 inhibitor. Subsequent evaluation of its analogs led to the identification of compound 668429, which exhibited the most potent antagonistic activity with an IC50 value of 0.52 µM under our assay conditions. Structure-activity relationship analysis revealed crucial functional groups and interactions responsible for FPR1 inhibitory activity. In addition, compound 668429 demonstrated selectivity for FPR1 over FPR2. In vitro assays confirmed that 668429 effectively inhibited FPR1-mediated neutrophil functions, including reactive oxygen species production, degranulation, and integrin expression. Moreover, 668429 suppressed downstream FPR1 signaling pathways involving calcium mobilization, MAPK activation, and AKT phosphorylation. Together, these results suggest that compound 668429 is a selective FPR1 inhibitor and a promising starting point for the development of therapeutics targeting neutrophil-driven inflammatory disorders.
Wang et al. (Wed,) studied this question.