Synthesis, enantioresolution, and activity profile of chiral 6-methyl-2,4-disubstituted pyridazin-3(2H)-ones as potent N-formyl peptide receptor agonists

Agostino Cilibrizzi, Igor A. Schepetkin, Gianluca Bartolucci, Letizia Crocetti, Vittorio Dal Piaz, Maria Paola Giovannoni, Alessia Graziano, Liliya N. Kirpotina, Mark T. Quinn, Claudia Vergelli

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3781-3792
Number of pages12
JournalBioorganic and Medicinal Chemistry
Volume20
Issue number12
DOIs
Publication statusPublished - 15 Jun 2012
Externally publishedYes

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Keywords

  • Chiral agonists
  • Enantiomers
  • Formyl peptide receptors
  • Inflammation
  • Neutrophils
  • Pyridazin-3(2H)-ones

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

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