title: Further studies on 2-arylacetamide pyridazin-3(2H)-ones: design, synthesis and evaluation of 4,6-disubstituted analogs as formyl peptide receptors (FPRs) agonists.
abstract: Formyl peptide receptors (FPRs) play an essential role in the regulation of endogenous inflammation and immunity. In the present studies, a large series of pyridazin-3(2H)-one derivatives bearing an arylacetamide chain at position 2 was synthesized and tested for FPR agonist activity. The pyridazin-3(2H)-one ring was confirmed to be an appropriate scaffold to support FPR agonist activity, and its modification at the 4 and 6 positions led to the identification of additional active agonists, which induced intracellular Ca(2+) flux in HL-60 cells transfected with either FPR1, FPR2, or FPR3. Seven formyl peptide receptor 1 (FPR1)-specific and several mixed FPR1/FPR2 dual agonists were identified with low micromolar EC50 values. Furthermore, these agonists also activated human neutrophils, inducing intracellular Ca(2+) flux and chemotaxis. Finally, molecular docking studies indicated that the most potent pyridazin-3(2H)-ones overlapped in their best docking poses with fMLF and WKYMVM peptides in the FPR1 and FPR2 ligand binding sites, respectively. Thus, pyridazinone-based compounds represent potential lead compounds for further development of selective and/or potent FPR agonists.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Firenze, Italy. mariapaola.giovannoni@unifi.it
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Giovannoni
authors.forename: Igor A
authors.initials: IA
authors.lastname: Schepetkin
authors.forename: Agostino
authors.initials: A
authors.lastname: Cilibrizzi
authors.forename: Letizia
authors.initials: L
authors.lastname: Crocetti
authors.forename: Andrei I
authors.initials: AI
authors.lastname: Khlebnikov
authors.forename: Claes
authors.initials: C
authors.lastname: Dahlgren
authors.forename: Alessia
authors.initials: A
authors.lastname: Graziano
authors.forename: Vittorio
authors.initials: V
authors.lastname: Dal Piaz
authors.forename: Liliya N
authors.initials: LN
authors.lastname: Kirpotina
authors.forename: Serena
authors.initials: S
authors.lastname: Zerbinati
authors.forename: Claudia
authors.initials: C
authors.lastname: Vergelli
authors.forename: Mark T
authors.initials: MT
authors.lastname: Quinn
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D018922:HL-60 Cells; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D044042:Receptors, Formyl Peptide / Q000819:agonists*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000081:Acetamides; D000970:Antineoplastic Agents; D011724:Pyridazines; D044042:Receptors, Formyl Peptide