title: Synthesis, enantioresolution, and activity profile of chiral 6-methyl-2,4-disubstituted pyridazin-3(2H)-ones as potent N-formyl peptide receptor agonists.
abstract: A series of chiral pyridazin-3(2H)-ones was synthesized, separated as pure enantiomers, and evaluated for N-formyl peptide receptor (FPR) agonist activity. Characterization of the purified enantiomers using combined chiral HPLC and chiroptical studies (circular dichroism, allowed unambiguous assignment of the absolute configuration for each pair of enantiomers). Evaluation of the ability of racemic mixtures and purified enantiomers to stimulate intracellular Ca(2+) flux in FPR-transfected HL-60 cells and human neutrophils and to induce β-arrestin recruitment in FPR-transfected CHO-K1 cells showed that many enantiomers were potent agonists, inducing responses in the sub-micromolar to nanomolar range. Furthermore, FPRs exhibited enantiomer selectivity, generally preferring the R-(-)-forms over the S-(+)-enantiomers. Finally, we found that elongation of the carbon chain in the chiral center of the active compounds generally increased biological activity. Thus, these studies provide important new information regarding molecular features involved in FPR ligand preference and report the identification of a novel series of FPR agonists.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Firenze, Via Ugo Schiff 6, Sesto Fiorentino 50019, Italy.
authors.forename: Agostino
authors.initials: A
authors.lastname: Cilibrizzi
authors.forename: Igor A
authors.initials: IA
authors.lastname: Schepetkin
authors.forename: Gianluca
authors.initials: G
authors.lastname: Bartolucci
authors.forename: Letizia
authors.initials: L
authors.lastname: Crocetti
authors.forename: Vittorio
authors.initials: V
authors.lastname: Dal Piaz
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Giovannoni
authors.forename: Alessia
authors.initials: A
authors.lastname: Graziano
authors.forename: Liliya N
authors.initials: LN
authors.lastname: Kirpotina
authors.forename: Mark T
authors.initials: MT
authors.lastname: Quinn
authors.forename: Claudia
authors.initials: C
authors.lastname: Vergelli
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D018922:HL-60 Cells; D006801:Humans; D008958:Models, Molecular; D009504:Neutrophils; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D044042:Receptors, Formyl Peptide / Q000819:agonists*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D011724:Pyridazines; D044042:Receptors, Formyl Peptide