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.