Synthesis and Pharmacological Evaluation of New Pyridazin-Based Thioderivatives as Formyl Peptide Receptor (FPR) Agonists
Version of Record online: 24 MAY 2013
© 2013 Wiley Periodicals, Inc.
Drug Development Research
Volume 74, Issue 4, pages 259–271, June 2013
How to Cite
Crocetti, L., Vergelli, C., Cilibrizzi, A., Graziano, A., Khlebnikov, A. I., Kirpotina, L. N., Schepetkin, I. A., Quinn, M. T. and Giovannoni, M. P. (2013), Synthesis and Pharmacological Evaluation of New Pyridazin-Based Thioderivatives as Formyl Peptide Receptor (FPR) Agonists. Drug Dev. Res., 74: 259–271. doi: 10.1002/ddr.21076
- Issue online: 10 JUN 2013
- Version of Record online: 24 MAY 2013
- Manuscript Accepted: 4 FEB 2013
- Manuscript Received: 23 JAN 2013
- National Institutes of Health. Grant Number: GM103500
- Montana State University Agricultural Experimental Station
- formyl peptide receptors;
- Ca2+ mobilization
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 Ca2+ 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.