interleukin-8 and pyrazole

N-formyl-methionyl-leucyl-phenylalanine (fMLF), its methyl ester fMLF-OMe and interleukin 8 (IL8) play a pivotal role in neutrophil chemotaxis regulation in the latter and early stages, respectively, but the mechanisms through which the signal transduction pathways activate this function are not yet completely understood. Compounds 3l and 3r, a new class of arylcarbamoyl-imidazo-pyrazoles derivatives, were described as the first example of compounds able to inhibit human neutrophil chemotaxis induced by both fMLF-OMe and IL8. Here, we report their effects on superoxide production and lysozyme release. No inhibition was observed, thus they could be defined as "pure" chemotactic antagonists. Therefore, such molecules were used to highlight specific kinases involved in neutrophil chemotaxis. Our data provide support that compounds 3l and 3r strongly inhibit p38 MAPK with either fMLF-OMe or IL8 chemoattractants, while they show different signaling pathways regarding PKC isoforms suggesting that a fine tuning of the neutrophil activation occurs through differences in the activation of signaling pathways. Neither fMLF-OMe nor IL8 were able to obtain activation of the PI3K/Akt pathway. Since anomalous activation of neutrophil recruitment is one of the causes of many inflammatory diseases, the good versatility of our derivatives could represent the most important characteristic of these new molecules in the development of novel therapeutics.

Topics: Chemotaxis; Humans; Imidazoles; Interleukin-8; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Pyrazoles; Signal Transduction; Structure-Activity Relationship; Superoxides

Anomalous activation of neutrophil recruitment is one of the causes of many inflammatory diseases. The chemoattractants N-formyl-methionyl-leucyl-phenylalanine (fMLP), and interleukine 8 (IL8) play a pivotal role in neutrophil chemotaxis regulation in the latter and early stages, respectively, probably by two independent mechanisms. We reported here synthesis and biological evaluation of new N-aryl-2-phenyl-2,3-dihydro-imidazo[1,2-b]pyrazole-1-carboxamides 7-substituted which were designed as possible multi-target antiinflammatory agents. Many of the title compounds showed a good inhibition, in the nano molar range, of human neutrophil chemotaxis selectively acting toward fMLP-OMe (methylester of fMLP) or IL8 stimulus; whereas, two compounds showed an interesting dual activity inhibiting both fMLP-OMe and IL8-induced chemotaxis at nano molar concentration.

Topics: Chemotaxis; Humans; Inhibitory Concentration 50; Interleukin-8; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Pyrazoles; Structure-Activity Relationship