Claudia Vergelli1, Igor A Schepetkin2, Giovanna Ciciani1, Agostino Cilibrizzi3, Letizia Crocetti1, Maria Paola Giovannoni4, Gabriella Guerrini1, Antonella Iacovone1, Liliya N Kirpotina2, Andrei I Khlebnikov5, Richard D Ye6, Mark T Quinn2. 1. Dipartimento di NEUROFARBA, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Firenze, Italy. 2. Department of Microbiology and Immunology, Montana State University, Bozeman, MT 59717, USA. 3. Department of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, UK. 4. Dipartimento di NEUROFARBA, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Firenze, Italy. Electronic address: mariapaola.giovannoni@unifi.it. 5. Department of Biotechnology and Organic Chemistry, Tomsk Polytechnic University, Tomsk 634050, Russia; Department of Chemistry, Altai State Technical University, Barnaul, Russia. 6. Institute of Chinese Medical Sciences, University of Macau, Macau.
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.
N-n class="Gene">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.
Authors: Igor A Schepetkin; Liliya N Kirpotina; Andrei I Khlebnikov; Ni Cheng; Richard D Ye; Mark T Quinn Journal: Biochem Pharmacol Date: 2014-10-17 Impact factor: 5.858
Authors: Maria Paola Giovannoni; Igor A Schepetkin; Agostino Cilibrizzi; Letizia Crocetti; Andrei I Khlebnikov; Claes Dahlgren; Alessia Graziano; Vittorio Dal Piaz; Liliya N Kirpotina; Serena Zerbinati; Claudia Vergelli; Mark T Quinn Journal: Eur J Med Chem Date: 2013-04-08 Impact factor: 6.514
Authors: Claudia Vergelli; Igor A Schepetkin; Giovanna Ciciani; Agostino Cilibrizzi; Letizia Crocetti; Maria Paola Giovannoni; Gabriella Guerrini; Antonella Iacovone; Liliya N Kirpotina; Richard D Ye; Mark T Quinn Journal: Drug Dev Res Date: 2016-11-18 Impact factor: 4.360
Authors: Letizia Crocetti; Claudia Vergelli; Gabriella Guerrini; Niccolò Cantini; Liliya N Kirpotina; Igor A Schepetkin; Mark T Quinn; Carmen Parisio; Lorenzo Di Cesare Mannelli; Carla Ghelardini; Maria Paola Giovannoni Journal: Bioorg Chem Date: 2020-04-28 Impact factor: 5.275
Authors: Niccolo Cantini; Igor A Schepetkin; Nadezhda V Danilenko; Andrei I Khlebnikov; Letizia Crocetti; Maria Paola Giovannoni; Liliya N Kirpotina; Mark T Quinn Journal: Molecules Date: 2022-06-10 Impact factor: 4.927
Authors: Letizia Crocetti; Claudia Vergelli; Gabriella Guerrini; Maria Paola Giovannoni; Liliya N Kirpotina; Andrei I Khlebnikov; Carla Ghelardini; Lorenzo Di Cesare Mannelli; Elena Lucarini; Igor A Schepetkin; Mark T Quinn Journal: Molecules Date: 2021-10-30 Impact factor: 4.411
Authors: Niccolò Cantini; Andrei I Khlebnikov; Letizia Crocetti; Igor A Schepetkin; Giuseppe Floresta; Gabriella Guerrini; Claudia Vergelli; Gianluca Bartolucci; Mark T Quinn; Maria Paola Giovannoni Journal: Bioorg Med Chem Date: 2020-11-06 Impact factor: 3.641
Authors: Claudia Vergelli; Andrei I Khlebnikov; Letizia Crocetti; Gabriella Guerrini; Niccolò Cantini; Liliya N Kirpotina; Igor A Schepetkin; Agostino Cilibrizzi; Mark T Quinn; Patrizia Rossi; Paola Paoli; Maria Paola Giovannoni Journal: Chem Biol Drug Des Date: 2021-07-01 Impact factor: 2.817