title: Synthesis of Five- and Six-Membered N-Phenylacetamido Substituted Heterocycles as Formyl Peptide Receptor Agonists.
abstract: 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. Drug Dev Res 78 : 49-62, 2017. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of NEUROFARBA, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff 6, Sesto, Fiorentino, 50019, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Vergelli
authors.affiliation: Department of Microbiology and Immunology, Montana State University, Bozeman, Montana 59717.
authors.forename: Igor A
authors.initials: IA
authors.lastname: Schepetkin
authors.affiliation: Department of NEUROFARBA, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff 6, Sesto, Fiorentino, 50019, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Ciciani
authors.affiliation: Department of Chemistry, Imperial College London, South Kensington, London, SW7 2AZ, United Kingdom.
authors.forename: Agostino
authors.initials: A
authors.lastname: Cilibrizzi
authors.affiliation: Department of NEUROFARBA, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff 6, Sesto, Fiorentino, 50019, Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Crocetti
authors.affiliation: Department of NEUROFARBA, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff 6, Sesto, Fiorentino, 50019, Italy.
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Giovannoni
authors.affiliation: Department of NEUROFARBA, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff 6, Sesto, Fiorentino, 50019, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Guerrini
authors.affiliation: Department of NEUROFARBA, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff 6, Sesto, Fiorentino, 50019, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Iacovone
authors.affiliation: Department of Microbiology and Immunology, Montana State University, Bozeman, Montana 59717.
authors.forename: Liliya N
authors.initials: LN
authors.lastname: Kirpotina
authors.affiliation: Institute of Chinese Medical Sciences, University of Macau, Macau, China.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Ye
authors.affiliation: Department of Microbiology and Immunology, Montana State University, Bozeman, Montana 59717.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Quinn
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D044042:Receptors, Formyl Peptide / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D006571:Heterocyclic Compounds; D044042:Receptors, Formyl Peptide
keywords: Ca2+ flux; agonist; formyl peptide receptor; neutrophil; pyridazin-3(2H)-one