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

15 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

Fingerprint

Formyl Peptide Receptor
Trp-Lys-Tyr-Met-Val-Met
Bearings (structural)
Fluxes
Lead compounds
HL-60 Cells
Chemotaxis
Scaffolds
Immunity
Neutrophils
Binding Sites
Ligands
Inflammation
Derivatives
Peptides

Keywords

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

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Pharmacology

Cite this

Further studies on 2-arylacetamide pyridazin-3(2H)-ones : Design, synthesis and evaluation of 4,6-disubstituted analogs as formyl peptide receptors (FPRs) agonists. / Giovannoni, Maria Paola; Schepetkin, Igor A.; Cilibrizzi, Agostino; Crocetti, Letizia; Khlebnikov, Andrey Ivanovich; Dahlgren, Claes; Graziano, Alessia; Dal Piaz, Vittorio; Kirpotina, Liliya N.; Zerbinati, Serena; Vergelli, Claudia; Quinn, Mark T.

In: European Journal of Medicinal Chemistry, Vol. 64, 2013, p. 512-528.

Research output: Contribution to journalArticle

Giovannoni, Maria Paola ; Schepetkin, Igor A. ; Cilibrizzi, Agostino ; Crocetti, Letizia ; Khlebnikov, Andrey Ivanovich ; Dahlgren, Claes ; Graziano, Alessia ; Dal Piaz, Vittorio ; Kirpotina, Liliya N. ; Zerbinati, Serena ; Vergelli, Claudia ; Quinn, Mark T. / Further studies on 2-arylacetamide pyridazin-3(2H)-ones : Design, synthesis and evaluation of 4,6-disubstituted analogs as formyl peptide receptors (FPRs) agonists. In: European Journal of Medicinal Chemistry. 2013 ; Vol. 64. pp. 512-528.
@article{b663b6e581674eb39d9fb1ed3c2156a0,
title = "Further studies on 2-arylacetamide pyridazin-3(2H)-ones: Design, synthesis and evaluation of 4,6-disubstituted analogs as formyl peptide receptors (FPRs) agonists",
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.",
keywords = "Dual agonist, Formyl peptide receptor, Human neutrophils, Molecular docking, Pyridazin-3(2H)-one",
author = "Giovannoni, {Maria Paola} and Schepetkin, {Igor A.} and Agostino Cilibrizzi and Letizia Crocetti and Khlebnikov, {Andrey Ivanovich} and Claes Dahlgren and Alessia Graziano and {Dal Piaz}, Vittorio and Kirpotina, {Liliya N.} and Serena Zerbinati and Claudia Vergelli and Quinn, {Mark T.}",
year = "2013",
doi = "10.1016/j.ejmech.2013.03.066",
language = "English",
volume = "64",
pages = "512--528",
journal = "European Journal of Medicinal Chemistry",
issn = "0223-5234",
publisher = "Elsevier Masson SAS",

}

TY - JOUR

T1 - Further studies on 2-arylacetamide pyridazin-3(2H)-ones

T2 - Design, synthesis and evaluation of 4,6-disubstituted analogs as formyl peptide receptors (FPRs) agonists

AU - Giovannoni, Maria Paola

AU - Schepetkin, Igor A.

AU - Cilibrizzi, Agostino

AU - Crocetti, Letizia

AU - Khlebnikov, Andrey Ivanovich

AU - Dahlgren, Claes

AU - Graziano, Alessia

AU - Dal Piaz, Vittorio

AU - Kirpotina, Liliya N.

AU - Zerbinati, Serena

AU - Vergelli, Claudia

AU - Quinn, Mark T.

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

KW - Dual agonist

KW - Formyl peptide receptor

KW - Human neutrophils

KW - Molecular docking

KW - Pyridazin-3(2H)-one

UR - http://www.scopus.com/inward/record.url?scp=84877838713&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84877838713&partnerID=8YFLogxK

U2 - 10.1016/j.ejmech.2013.03.066

DO - 10.1016/j.ejmech.2013.03.066

M3 - Article

VL - 64

SP - 512

EP - 528

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

ER -