Browsing by Author "Cilibrizzi, Agostino"

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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.
Synthesis and analytical characterization of new thiazol-2-(3H)-ones as human neutrophil elastase (HNE) inhibitors
(2018-01) Crocetti, Letizia; Bartolucci, Gianluca; Cilibrizzi, Agostino; Giovannoni, Maria Paola; Guerrini, Gabriella; Iacovone, Antonella; Menicatti, Marta; Schepetkin, Igor A.; Khlebnikov, Andrei I.; Quinn, Mark T.; Vergelli, Claudia
Human neutrophil elastase (HNE) is a potent serine protease belonging to the chymotrypsin family and is involved in a variety of pathologies affecting the respiratory system. Thus, compounds able to inhibit HNE proteolytic activity could represent effective therapeutics. We present here the synthesis of new thiazol-2-(3H)-ones as an elaboration of potent HNE inhibitors with an isoxazol-5-(2H)-one scaffold that we recently identified. Two-dimensional NMR spectroscopic techniques and tandem mass spectrometry allowed us to correctly assign the structure of the final compounds arising from both tautomers of the thiazol-2-(3H)-one nucleus (N-3 of the thiazol-2-(3H)-one and 3-OH of the thiazole). All new compounds were tested as HNE inhibitors, and no activity was found at the highest concentration used (40 ÂµM), demonstrating that the thiazol-2-(3H)-one is not a good scaffold for HNE inhibitors. Molecular modelling experiments indicate that the low-energy pose might limit the nucleophilic attack on the endocyclic carbonyl group of the thiazolone-based compounds by HNE catalytic Ser195, in contrast to isoxazol-5-(2H)-one analogues.
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 â€‰=â€‰19 nM, FPR2 EC50 â€‰=â€‰43 nM, FPR3 EC50 â€‰=â€‰40 nM), and 4b, which had potent activity and a preference for FPR2 (EC50 â€‰=â€‰13 nM). These novel compounds may represent valuable tools for studying FPR activation and signaling.
Synthesis, biological evaluation, molecular modeling, and structural analysis of new pyrazole and pyrazolone derivatives as N-formyl peptide receptors agonists
(Wiley, 2021-06) Vergelli, Claudia; Khlebnikov, Andrei I.; Crocetti, Letizia; Guerrini, Gabriella; Cantini, Niccolò; Kirpotina, Liliya N.; Schepetkin, Igor A.; Cilibrizzi, Agostino; Quinn, Mark T.; Rossi, Patrizia; Paoli, Paola; Giovannoni, Maria Paola
N- formyl peptide receptors (FPR1, FPR2, and FPR3) play key roles in the regulation of inflammatory processes, and recently, it was demonstrated that FPR1 and FPR2 have a dual role in the progression/suppression of some cancers. Therefore, FPRs represent an important therapeutic target for the treatment of both cancer and inflammatory diseases. Previously, we identified selective or mixed FPR agonists with pyridazinone or pyridinone scaffolds showing a common 4-(bromophenyl)acetamide fragment, which was essential for activity. We report here new pyrazole and pyrazolone derivatives as restricted analogues of the above 6-membered compounds, all exhibiting the same 4-bromophenylacetamide side chain. Most new products had low or absent FPR agonist activity, suggesting that the pyrazole nucleus was not appropriate for FPR agonists. This hypothesis was confirmed by molecular modeling studies, which highlighted that the five-membered scaffold was responsible for a worse arrangement of the molecules in the receptor binding site.