title: 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 EC50values 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.affiliation: Dipartimento di NEUROFARBA, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Firenze, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Vergelli
authors.affiliation: Department of Microbiology and Immunology, Montana State University, Bozeman, MT 59717, USA.
authors.forename: Igor A
authors.initials: IA
authors.lastname: Schepetkin
authors.affiliation: Dipartimento di NEUROFARBA, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Firenze, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Ciciani
authors.affiliation: Department of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, UK.
authors.forename: Agostino
authors.initials: A
authors.lastname: Cilibrizzi
authors.affiliation: Dipartimento di NEUROFARBA, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Firenze, Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Crocetti
authors.affiliation: 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.
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Giovannoni
authors.affiliation: Dipartimento di NEUROFARBA, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Firenze, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Guerrini
authors.affiliation: Dipartimento di NEUROFARBA, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Firenze, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Iacovone
authors.affiliation: Department of Microbiology and Immunology, Montana State University, Bozeman, MT 59717, USA.
authors.forename: Liliya N
authors.initials: LN
authors.lastname: Kirpotina
authors.affiliation: Department of Biotechnology and Organic Chemistry, Tomsk Polytechnic University, Tomsk 634050, Russia; Department of Chemistry, Altai State Technical University, Barnaul, Russia.
authors.forename: Andrei I
authors.initials: AI
authors.lastname: Khlebnikov
authors.affiliation: Institute of Chinese Medical Sciences, University of Macau, Macau.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Ye
authors.affiliation: Department of Microbiology and Immunology, Montana State University, Bozeman, MT 59717, USA.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Quinn
keywords: Agonist; Ca(2+) mobilization; Formyl peptide receptor (FPR); Neutrophil; Pyridazin-3(2H)-one