Synthesis and biological evaluation of N-pyrazolyl-N'-alkyl/benzyl/phenylureas: a new class of potent inhibitors of interleukin 8-induced neutrophil chemotaxis

Neutrophil chemotaxis is a complex multistep process that, if upregulated, causes acute inflammation and a no. of autoimmune diseases. The synthesis of pyrazolyl ureas, e.g., I and II (R = 3-benzyl, 3-Ph, 3-iso-Pr), that are potent inhibitors of interleukin-8 (IL-8)-induced neutrophil chemotaxis, is reported. A series of compds., obtained by functionalization with a urea moiety of 5-amino-1-(2-hydroxy-2-phenylethyl)-1H-pyrazole-4-carboxylic acid Et ester, blocked the IL-8-induced neutrophil chemotaxis, while they did not block N-formylmethionylleucylphenylalanine-mediated chemotaxis. The most active compds., I and II, showed an IC50 of 14 and 10, 45, 55 nM, resp. Compds. II were inactive in the CXCR1 and CXCR2 (IL-8 receptors), whereas they inhibited the phosphorylation of PTKs (protein tyrosine kinases) in the 50-70 kDa. Moreover, a complete block of F-actin rise and pseudopod formation were obsd for compds. II. Several mols. with different substitutes were also synthesized to obtain more information for SAR study