Further studies on 2-arylacetamide pyridazin-3(2H)-ones: Design, synthesis and evaluation of 4,6-disubstituted analogs as formyl peptide receptors (FPRs) agonists

Maria Paola Giovannoni, Igor A. Schepetkin, Agostino Cilibrizzi, Letizia Crocetti, Andrey Ivanovich Khlebnikov, Claes Dahlgren, Alessia Graziano, Vittorio Dal Piaz, Liliya N. Kirpotina, Serena Zerbinati, Claudia Vergelli, Mark T. Quinn

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Formyl peptide receptors (FPRs) play an essential role in the regulation of endogenous inflammation and immunity. In the present studies, a large series of pyridazin-3(2H)-one derivatives bearing an arylacetamide chain at position 2 was synthesized and tested for FPR agonist activity. The pyridazin-3(2H)-one ring was confirmed to be an appropriate scaffold to support FPR agonist activity, and its modification at the 4 and 6 positions led to the identification of additional active agonists, which induced intracellular Ca2+ flux in HL-60 cells transfected with either FPR1, FPR2, or FPR3. Seven formyl peptide receptor 1 (FPR1)-specific and several mixed FPR1/FPR2 dual agonists were identified with low micromolar EC50 values. Furthermore, these agonists also activated human neutrophils, inducing intracellular Ca2+ flux and chemotaxis. Finally, molecular docking studies indicated that the most potent pyridazin-3(2H)-ones overlapped in their best docking poses with fMLF and WKYMVM peptides in the FPR1 and FPR2 ligand binding sites, respectively. Thus, pyridazinone-based compounds represent potential lead compounds for further development of selective and/or potent FPR agonists.

Original languageEnglish
Pages (from-to)512-528
Number of pages17
JournalEuropean Journal of Medicinal Chemistry
Volume64
DOIs
Publication statusPublished - 2013
Externally publishedYes

Keywords

  • Dual agonist
  • Formyl peptide receptor
  • Human neutrophils
  • Molecular docking
  • Pyridazin-3(2H)-one

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Pharmacology

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