Browsing by Author "Ciciani, Giovanna"
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Item 2-Arylacetamido-4-phenylamino-5-substituted pyridazinones as formyl peptide receptors agonists(2016-06) Vergelli, Claudia; Schepetkin, Igor A.; Ciciani, Giovanna; Cilibrizzi, Agostino; Crocetti, Letizia; Giovannoni, Maria Paola; Guerrini, Gabriella; Iacovone, Antonella; Kirpotina, Liliya N.; Khlebnikov, Andrei I.; Ye, Richard D.; Quinn, Mark T.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.Item Synthesis of Five- and Six-Membered N-Phenylacetamido Substituted Heterocycles as Formyl Peptide Receptor Agonists(2016-11) Vergelli, Claudia; Schepetkin, Igor A.; Ciciani, Giovanna; Cilibrizzi, Agostino; Crocetti, Letizia; Giovannoni, Maria Paola; Guerrini, Gabriella; Iacovone, Antonella; Kirpotina, Liliya N.; Ye, Richard D.; Quinn, Mark T.Preclinical Research Formyl peptide receptors (FPRs) are G-protein-coupled receptors that play an important role in the regulation of inflammatory process and cellular dysfunction. In humans, three different isoforms are expressed (FPR1, FPR2, and FPR3). FPR2 appears to be directly involved in the resolution of inflammation, an active process carried out by specific pro-resolving mediators that modulate specific receptors. Previously, we identified 2-arylacetamido pyridazin-3(2H)-ones as FPR1- or FPR2-selective agonists, as well as a large number of mixed-agonists for the three isoforms. Here, we report a new series of 2-arylacetamido pyridazinones substituted at position 5 and their development as FPR agonists. We also synthesized a new series of 2-oxothiazolones bearing a 4-bromophenylacetamido fragment, which was fundamental for activity in the pyridazinone series. The compounds of most interest were 4a, a potent, mixed FPR agonist recognized by all three isotypes (FPR1 EC50  = 19 nM, FPR2 EC50  = 43 nM, FPR3 EC50  = 40 nM), and 4b, which had potent activity and a preference for FPR2 (EC50  = 13 nM). These novel compounds may represent valuable tools for studying FPR activation and signaling.