title: 6-methyl-2,4-disubstituted pyridazin-3(2H)-ones: a novel class of small-molecule agonists for formyl peptide receptors.
abstract: Following a ligand-based drug design approach, a potent mixed formyl peptide receptor 1 (FPR1) and formyl peptide receptor-like 1 (FPRL1) agonist (14a) and a potent and specific FPRL1 agonist (14x) were identified. These compounds belong to a large series of pyridazin-3(2H)-one derivatives substituted with a methyl group at position 6 and a methoxy benzyl at position 4. At position 2, an acetamide side chain is essential for activity. Likewise, the presence of lipophilic and/or electronegative substituents in the position para to the aryl group at the end of the chain plays a critical role for activity. Affinity for FPR1 receptors was evaluated by measuring intracellular calcium flux in HL-60 cells transfected with FPR1, FPRL1, and FPRL2. Agonists were able to activate intracellular calcium mobilization and chemotaxis in human neutrophils. The most potent chemotactic agent (EC(50) = 0.6 microM) was the mixed FPR/FPRL1 agonist 14h.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Universita degli Studi di Firenze, Via Ugo Schiff 6, Sesto Fiorentino 50019 Firenze, Italy.
authors.forename: Agostino
authors.initials: A
authors.lastname: Cilibrizzi
authors.forename: Mark T
authors.initials: MT
authors.lastname: Quinn
authors.forename: Liliya N
authors.initials: LN
authors.lastname: Kirpotina
authors.forename: Igor A
authors.initials: IA
authors.lastname: Schepetkin
authors.forename: Jeff
authors.initials: J
authors.lastname: Holderness
authors.forename: Richard D
authors.initials: RD
authors.lastname: Ye
authors.forename: Marie-Josephe
authors.initials: MJ
authors.lastname: Rabiet
authors.forename: Claudio
authors.initials: C
authors.lastname: Biancalani
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Cesari
authors.forename: Alessia
authors.initials: A
authors.lastname: Graziano
authors.forename: Claudia
authors.initials: C
authors.lastname: Vergelli
authors.forename: Stefano
authors.initials: S
authors.lastname: Pieretti
authors.forename: Vittorio
authors.initials: V
authors.lastname: Dal Piaz
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Giovannoni
mesh_terms: D002118:Calcium / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D066298:In Vitro Techniques; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D044042:Receptors, Formyl Peptide / Q000819:agonists*; D044067:Receptors, Lipoxin / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: C550437:2-(5-(3-methoxybenzyl)-3-methyl-6-oxo-6H-pyridazin-1-yl)-N-4-tolyl-acetamide; C469986:FPR1 protein, human; C105101:FPR2 protein, human; C469985:FPR3 protein, human; D011724:Pyridazines; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; D002118:Calcium