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

Fingerprint

Formyl Peptide Receptor
Enantiomers
Arrestin
CHO Cells
HL-60 Cells
Circular Dichroism
Neutrophils
Carbon
Dichroism
High Pressure Liquid Chromatography
Bioactivity
Ligands
Elongation
Fluxes

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

Cite this

Synthesis, enantioresolution, and activity profile of chiral 6-methyl-2,4-disubstituted pyridazin-3(2H)-ones as potent N-formyl peptide receptor agonists. / Cilibrizzi, Agostino; Schepetkin, Igor A.; Bartolucci, Gianluca; Crocetti, Letizia; Dal Piaz, Vittorio; Giovannoni, Maria Paola; Graziano, Alessia; Kirpotina, Liliya N.; Quinn, Mark T.; Vergelli, Claudia.

In: Bioorganic and Medicinal Chemistry, Vol. 20, No. 12, 15.06.2012, p. 3781-3792.

Research output: Contribution to journalArticle

Cilibrizzi, A, Schepetkin, IA, Bartolucci, G, Crocetti, L, Dal Piaz, V, Giovannoni, MP, Graziano, A, Kirpotina, LN, Quinn, MT & Vergelli, C 2012, 'Synthesis, enantioresolution, and activity profile of chiral 6-methyl-2,4-disubstituted pyridazin-3(2H)-ones as potent N-formyl peptide receptor agonists', Bioorganic and Medicinal Chemistry, vol. 20, no. 12, pp. 3781-3792. https://doi.org/10.1016/j.bmc.2012.04.043
Cilibrizzi, Agostino ; Schepetkin, Igor A. ; Bartolucci, Gianluca ; Crocetti, Letizia ; Dal Piaz, Vittorio ; Giovannoni, Maria Paola ; Graziano, Alessia ; Kirpotina, Liliya N. ; Quinn, Mark T. ; Vergelli, Claudia. / Synthesis, enantioresolution, and activity profile of chiral 6-methyl-2,4-disubstituted pyridazin-3(2H)-ones as potent N-formyl peptide receptor agonists. In: Bioorganic and Medicinal Chemistry. 2012 ; Vol. 20, No. 12. pp. 3781-3792.
@article{e083e0ebd187414bbab65a689f9098bb,
title = "Synthesis, enantioresolution, and activity profile of chiral 6-methyl-2,4-disubstituted pyridazin-3(2H)-ones as potent N-formyl peptide receptor agonists",
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.",
keywords = "Chiral agonists, Enantiomers, Formyl peptide receptors, Inflammation, Neutrophils, Pyridazin-3(2H)-ones",
author = "Agostino Cilibrizzi and Schepetkin, {Igor A.} and Gianluca Bartolucci and Letizia Crocetti and {Dal Piaz}, Vittorio and Giovannoni, {Maria Paola} and Alessia Graziano and Kirpotina, {Liliya N.} and Quinn, {Mark T.} and Claudia Vergelli",
year = "2012",
month = "6",
day = "15",
doi = "10.1016/j.bmc.2012.04.043",
language = "English",
volume = "20",
pages = "3781--3792",
journal = "Bioorganic and Medicinal Chemistry",
issn = "0968-0896",
publisher = "Elsevier Limited",
number = "12",

}

TY - JOUR

T1 - Synthesis, enantioresolution, and activity profile of chiral 6-methyl-2,4-disubstituted pyridazin-3(2H)-ones as potent N-formyl peptide receptor agonists

AU - Cilibrizzi, Agostino

AU - Schepetkin, Igor A.

AU - Bartolucci, Gianluca

AU - Crocetti, Letizia

AU - Dal Piaz, Vittorio

AU - Giovannoni, Maria Paola

AU - Graziano, Alessia

AU - Kirpotina, Liliya N.

AU - Quinn, Mark T.

AU - Vergelli, Claudia

PY - 2012/6/15

Y1 - 2012/6/15

N2 - 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.

AB - 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.

KW - Chiral agonists

KW - Enantiomers

KW - Formyl peptide receptors

KW - Inflammation

KW - Neutrophils

KW - Pyridazin-3(2H)-ones

UR - http://www.scopus.com/inward/record.url?scp=84861571323&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84861571323&partnerID=8YFLogxK

U2 - 10.1016/j.bmc.2012.04.043

DO - 10.1016/j.bmc.2012.04.043

M3 - Article

VL - 20

SP - 3781

EP - 3792

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

SN - 0968-0896

IS - 12

ER -