Synthesis and pharmacological evaluation of new pyridazin-based thioderivatives as formyl peptide receptor (FPR) agonists

Letizia Crocetti, Claudia Vergelli, Agostino Cilibrizzi, Alessia Graziano, Andrey Ivanovich Khlebnikov, Liliya N. Kirpotina, Igor A. Schepetkin, Mark T. Quinn, Maria Paola Giovannoni

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Preclinical Research A new series of pyridazinone-based thioderivatives and pyridazine analogs was synthesized and tested for their ability to bind to the three human formyl peptide receptor (FPR) isoforms (FPR1, FPR2, and FPR3) and to activate intracellular calcium mobilization and chemotaxis in human neutrophils. Among the pyridazin-3(2H)-one derivatives tested, analogs 8b and 8c were mixed FPR1/FPR2 agonists, with median effective concentration values in the micromolar range, and were able to activate chemotaxis and Ca 2+ flux in human neutrophils in the low micromolar range. Molecular docking studies showed that interaction of a ligand with Arg205 of FPR1 is important for FPR1 agonist activity. For FPR2, differences in activity between oxygen-containing compounds and their thio-analogs were due to steric bulkiness of sulfur-containing groups.

Original languageEnglish
Pages (from-to)259-271
Number of pages13
JournalDrug Development Research
Volume74
Issue number4
DOIs
Publication statusPublished - Jun 2013
Externally publishedYes

Fingerprint

Formyl Peptide Receptor
Pharmacology
Chemotaxis
Neutrophils
Oxygen Compounds
Aptitude
Sulfur
Protein Isoforms
Ligands
Calcium
Research

Keywords

  • Ca mobilization
  • chemotaxis
  • formyl peptide receptors
  • neutrophil
  • pyridazin-3(2H)-one
  • pyridazine

ASJC Scopus subject areas

  • Drug Discovery

Cite this

Synthesis and pharmacological evaluation of new pyridazin-based thioderivatives as formyl peptide receptor (FPR) agonists. / Crocetti, Letizia; Vergelli, Claudia; Cilibrizzi, Agostino; Graziano, Alessia; Khlebnikov, Andrey Ivanovich; Kirpotina, Liliya N.; Schepetkin, Igor A.; Quinn, Mark T.; Giovannoni, Maria Paola.

In: Drug Development Research, Vol. 74, No. 4, 06.2013, p. 259-271.

Research output: Contribution to journalArticle

Crocetti, Letizia ; Vergelli, Claudia ; Cilibrizzi, Agostino ; Graziano, Alessia ; Khlebnikov, Andrey Ivanovich ; Kirpotina, Liliya N. ; Schepetkin, Igor A. ; Quinn, Mark T. ; Giovannoni, Maria Paola. / Synthesis and pharmacological evaluation of new pyridazin-based thioderivatives as formyl peptide receptor (FPR) agonists. In: Drug Development Research. 2013 ; Vol. 74, No. 4. pp. 259-271.
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