Synthesis and Biological Evaluation of N-Pyrazolyl-N‘-alkyl/benzyl/phenylureas:  a New Class of Potent Inhibitors of Interleukin 8-Induced Neutrophil Chemotaxis

Abstract

Neutrophils chemotaxis is a complex multistep process that, if upregulated, causes acute inflammation and a number of autoimmune diseases. We report here the synthesis of a new N-(4-substituted)pyrazolyl-N'-alkyl/benzyl/phenylureas that are potent inhibitors of interleukin-8 (IL8)-induced neutrophil chemotaxis. The first series of compounds, obtained by functionalization with a urea moiety of the 5-amino-1-(2-hydroxy-2-phenylethyl)-1H-pyrazole-4-carboxylic acid ethyl ester 3, blocked the IL8-induced neutrophil chemotaxis, while they did not block N-formylmethionylleucylphenylalanine-mediated chemotaxis. The most active compounds, 3-benzyl- (4d), 3-(4-benzylpiperazinyl)- (4i), 3-phenyl- (4k) and 3-isopropylureido (4a) derivatives, showed an IC50 of 10, 14, 45, and 55 nM, respectively. Several different molecules were then synthesized to obtain more information for SAR study. Compounds 4a, 4d, and 4k were inactive in the binding assays on CXCR1 and CXCR2 (IL8 receptors), whereas they inhibited the phosphorylation of PTKs (protein tyrosine kinases) in the 50-70 kDa region. Moreover, in the presence of the same derivatives, we observed a complete block of F-actin rise and pseudopod formation.

Molecular Characterization of c-Abl/c-Src Kinase Inhibitors Targeted against Murine Tumour Progenitor Cells that Express Stem Cell Markers

“…The 5-amino-1-(2-hydroxy-2-phenylethyl)-1 H -pyrazole-4-carboxamide 6 , prepared according to our procedure [89], was treated with sodium ethoxide and ethyl acetate in absolute ethanol at reflux for 6 h to afford the 1-(2-hydroxy-2-phenylethyl)-6-methyl-1,5-dihydro-4 H -pyrazolo[3,4- d ]pyrimidin-4-one 7 , that was in turn chlorinated with the Vilsmeier complex (POCl 3 ∶DMF, 1∶1, 30 equiv), in refluxing CHCl 3 at reflux for 12 h to obtain the dichloro derivative 8 . Reaction of the latter with the suitable aniline in absolute ethanol at reflux for 4 h gave the desired compounds 9 and 10 (method A).…”

New Hybrid Pyrazole and Imidazopyrazole Antinflammatory Agents Able to Reduce ROS Production in Different Biological Targets

“…A multi-target compound can be designed by combining two different molecules (obtaining "chimera" compound) or by overlapping two pharmacophore fragments (obtaining "fused" or "hybrid" molecule). Our previous research on the antiinflammatory agent topic allowed us to identify different pyrazolylureas 1 and imidazopyrazoles 2 (Figure 1) able to inhibit the neutrophil movement towards inflamed tissues (chemotaxis inhibitors) with IC 50 values in the pico-micromolar range [3][4][5]. Pyrazolylureas 1 inhibited only interleukin 8 (IL8)-induced chemotaxis while imidazopyrazoles 2 inhibited only formylmethyl-leucyl-phenylalanine (fMLP)-induced chemotaxis.…”

Synthesis, enantioresolution, and activity profile of chiral 6-methyl-2,4-disubstituted pyridazin-3(2H)-ones as potent N-formyl peptide receptor agonists

“…1 However, if an injurious agent persists or disrupts leukocyte recruitment, both acute and chronic inflammatory disorders may ensue. 2 Indeed, dysregulated inflammatory processes play an important role in many diseases, such as asthma, 3 rheumatoid arthritis, multiple sclerosis, periodontal disease, cancer, cardiovascular and Alzheimer’s diseases. 4 Thus, the host inflammatory response requires stringent regulation to avoid self-induced damage, 5 and anti-inflammatory drugs are used to treat such inflammatory syndromes.…”