Synthesis and Pharmacological Evaluation of New Pyridazin-Based Thioderivatives as Formyl Peptide Receptor ( FPR) Agonists.

A new series of pyridazinone-based thioderivatives and pyridazine analogs was synthesizedand 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 chemotaxisand Ca2+ flux in human neutrophils in the low micromolar range. Molecular docking studies showed thatinteraction of a ligand with Arg205 of FPR1 is important for FPR1 agonist activity. For FPR2, differences inactivity between oxygen-containing compounds and their thio-analogs were due to steric bulkiness ofsulfur-containing groups. Drug Dev Res 74 : 259-271, 2013. [ABSTRACT FROM AUTHOR]