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.

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

SPISANI, Susanna;Falzarano MS;VARANI, Katia;
2009

Abstract

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.
Bruno, O; Brullo, C; Bondavalli, F; Schenone, S; Spisani, Susanna; Falzarano, Ms; Varani, Katia; Barocelli, E; Ballabeni, V; Giorgio, C; Tognolini, M.
File in questo prodotto:
File Dimensione Formato  
1-Methyl and 1-(2-hydroxyalkyl)-5-.pdf

solo gestori archivio

Descrizione: versione editoriale
Tipologia: Full text (versione editoriale)
Licenza: NON PUBBLICO - Accesso privato/ristretto
Dimensione 483.88 kB
Formato Adobe PDF
483.88 kB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/1377474
Citazioni
  • ???jsp.display-item.citation.pmc??? 6
  • Scopus 17
  • ???jsp.display-item.citation.isi??? 17
social impact