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 language | English |
|---|---|
| Pages (from-to) | 512-528 |
| Number of pages | 17 |
| Journal | European Journal of Medicinal Chemistry |
| Volume | 64 |
| DOIs | |
| Publication status | Published - 2013 |
| Externally published | Yes |
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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 journal › Article
}
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
C2 - 23685570
AN - SCOPUS:84877838713
VL - 64
SP - 512
EP - 528
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0223-5234
ER -