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

Результат исследований: Материалы для журналаСтатья

12 Цитирования (Scopus)

Выдержка

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.

Язык оригиналаАнглийский
Страницы (с-по)259-271
Число страниц13
ЖурналDrug Development Research
Том74
Номер выпуска4
DOI
СостояниеОпубликовано - июн 2013
Опубликовано для внешнего пользованияДа

Отпечаток

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

ASJC Scopus subject areas

  • Drug Discovery

Цитировать

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.

В: Drug Development Research, Том 74, № 4, 06.2013, стр. 259-271.

Результат исследований: Материалы для журналаСтатья

Crocetti, L, Vergelli, C, Cilibrizzi, A, Graziano, A, Khlebnikov, AI, Kirpotina, LN, Schepetkin, IA, Quinn, MT & Giovannoni, MP 2013, 'Synthesis and pharmacological evaluation of new pyridazin-based thioderivatives as formyl peptide receptor (FPR) agonists', Drug Development Research, том. 74, № 4, стр. 259-271. https://doi.org/10.1002/ddr.21076
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. В: Drug Development Research. 2013 ; Том 74, № 4. стр. 259-271.
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AU - Khlebnikov, Andrey Ivanovich

AU - Kirpotina, Liliya N.

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AB - 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.

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