Bioorganic and Medicinal Chemistry p. 3379 - 3387 (2009)
Update date:2022-08-04
Topics:
Bruno, Olga
Brullo, Chiara
Bondavalli, Francesco
Schenone, Silvia
Spisani, Susanna
Falzarano, Maria Sofia
Varani, Katia
Barocelli, Elisabetta
Ballabeni, Vigilio
Giorgio, Carmine
Tognolini, Massimiliano
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.
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