Targeting Neutrophil-Mediated Inflammation: Identification of Pyrazolidinone Carboxamide Derivatives as Potent Selective Inhibitors of Formyl Peptide Receptor 1 (FPR1)-Activated Neutrophils

Neutrophils play a critical role in the innate immune response, but their overactivation can lead to chronic inflammation and tissue damage in conditions such as rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), and sepsis. Formyl peptide receptor 1 (FPR1) is a key regulator of neutrophil activation, making it an attractive target for therapeutic intervention. In this study, an in-house screening revealed pyrazolidinone carboxamide derivatives as effective inhibitors of neutrophil activation, exhibiting no cytotoxic effects. Compounds 10-12 and 21 demonstrated selective inhibition of FPR1-induced neutrophil superoxide anion production and elastase release with submicromolar IC50 values, while having no effect on the FPR2 pathway. On a structural level, electron-withdrawing groups on the thiazole ring within the amide side chain were found to be crucial for high potency. Binding assays confirmed that compounds 10, 11 and 21 act as direct antagonists of FPR1. In the LPS-induced acute respiratory distress syndrom (ARDS) model in mice, compound 10 significantly reduced pulmonary inflammation, oxidative stress, and neutrophil elastase activity, while showing no signs of toxicity in the liver or kidneys at the tested doses, highlighting its protective effects. Furthermore, molecular docking and dynamic simulations provided insights into their binding poses, explaining their interactions with key residues within the FPR1 binding site. This study lays the foundation for optimizing this class of compounds as therapeutic agents for controlling neutrophil-mediated inflammation.