title: Synthesis, HPLC enantioresolution, and X-ray analysis of a new series of C5-methyl pyridazines as N-formyl peptide receptor (FPR) agonists.
abstract: The synthesis of three racemates and the corresponding non-chiral analogues of a C5-methyl pyridazine series is described here, as well as the isolation of pure enantiomers and their absolute configuration assignment. In order to obtain optically active compounds, direct chromatographic methods of separation by HPLC-UV were investigated using four chiral stationary phases (CSPs: Lux Amylose-2, Lux Cellulose-1, Lux Cellulose-2 and Lux Cellulose-3). The best resolution was achieved using amylose tris(5-chloro-2-methylphenylcarbamate) (Lux Amylose-2), and single enantiomers were isolated on a semipreparative scale with high enantiomeric excess, suitable for biological assays. The absolute configuration of optically active compounds was unequivocally established by X-ray crystallographic analysis and comparative chiral HPLC-UV profile. All compounds of the series were tested for formyl peptide receptor (FPR) agonist activity, and four were found to be active, with EC50 values in the micromolar range.
authors.affiliation: Università degli Studi di Firenze, Dipartimento di Scienze Farmaceutiche, Via Ugo Schiff 6, Sesto Fiorentino, 50019, Firenze, Italy.
authors.forename: Agostino
authors.initials: A
authors.lastname: Cilibrizzi
authors.forename: Letizia
authors.initials: L
authors.lastname: Crocetti
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Giovannoni
authors.forename: Alessia
authors.initials: A
authors.lastname: Graziano
authors.forename: Claudia
authors.initials: C
authors.lastname: Vergelli
authors.forename: Gianluca
authors.initials: G
authors.lastname: Bartolucci
authors.forename: Giacomo
authors.initials: G
authors.lastname: Soldani
authors.forename: Mark T
authors.initials: MT
authors.lastname: Quinn
authors.forename: Igor A
authors.initials: IA
authors.lastname: Schepetkin
authors.forename: Cristina
authors.initials: C
authors.lastname: Faggi
mesh_terms: D060326:Chemistry Techniques, Synthetic; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D018922:HL-60 Cells; D006801:Humans; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D044042:Receptors, Formyl Peptide / Q000819:agonists*; D013237:Stereoisomerism
chemical_list: D011724:Pyridazines; D044042:Receptors, Formyl Peptide
keywords: FPRs; Lux Amylose; Lux Cellulose; absolute configuration; chiral stationary phase; inflammation; liquid chromatography; pyridazinones