2-Arylacetamido-4-phenylamino-5-substituted pyridazinones as formyl peptide receptors agonists

Abstract

N-Formyl peptide receptors (FPRs: FPR1, FPR2, and FPR3) are G protein-coupled receptors that play key roles in modulating immune cells. FPRs represent potentially important therapeutic targets for the development of drugs that could enhance endogenous anti-inflammation systems associated with various pathologies, thereby reducing the progression of inflammatory conditions. Previously, we identified 2-arylacetamide pyridazin-3(2H)-ones as FPR1- or FPR2-selective agonists, as well as a large number of FPR1/FPR2-dual agonists and several mixed-agonists for the three FPR isoforms. Here, we report a new series of 2-arylacetamido-4-aniline pyridazin-3(2H)-ones substituted in position 5 as a further development of these FPR agonists. Chemical manipulation presented in this work resulted in mixed FPR agonists 8a, 13a and 27b, which had EC₅₀ values in nanomolar range. In particular, compound 8a showed a preference for FPR1 (EC₅₀=45nM), while 13a and 27b showed a moderate preference for FPR2 (EC₅₀=35 and 61nM, respectively). Thus, these compounds may represent valuable tools for studying FPR activation and signaling.

Keywords: Agonist; Ca(2+) mobilization; Formyl peptide receptor (FPR); Neutrophil; Pyridazin-3(2H)-one.