1-Methyl and 1-(2-hydroxyalkyl)-5-(3-alkyl/cycloalkyl/phenyl/naphthylureido)-1H-pyrazole-4-carboxylic acid ethyl esters as potent human neutrophil chemotaxis inhibitors

In this paper we report the synthesis and the chemotaxis inhibitory activity of a number of 1H-pyrazole-4-carboxylic acid ethyl esters 2 functionalized in N1 with a methyl group or different hydroxyalkyl chains and in position 5 with a series of 3-substituted urea groups. These compounds were designed as development of previous pyrazole-urea derivatives that resulted potent IL8-induced neutrophil chemotaxis inhibitors in vitro. Most of the new compounds revealed a potent inhibition of both IL8- and fMLP-OMe-stimulated neutrophil chemotaxis. The most active compounds in the fMLP-OMe induced chemotaxis test showed IC50 in the range 0.19 nM–2 μM; but we observed a very strong inhibition in the IL8-induced chemotaxis test, having the most active compounds IC50 at pM concentrations. In vivo compounds 2e and 2f, although to a lesser extent, at 50 mg/kg os decreased granulocyte infiltration in zymosan-induced peritonitis in mice.

Title compounds showed a very strong inhibition both in the fMLP-OMe induced (IC50 in the range 0.19 nM–2 mM) and in IL8-induced (IC50 at pM concentration) neutrophil chemotaxis.The 2-fluoro and 3-fluoroanilino derivatives showed anti-inflammatory activity in vivo, in the mouse model of zymosan-induced peritonitis.Figure optionsDownload as PowerPoint slide