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 IC(50) in the range 0.19 nM-2 microM; but we observed a very strong inhibition in the IL8-induced chemotaxis test, having the most active compounds IC(50) at pM concentrations. In vivo compounds 2e and 2f, although to a lesser extent, at 50mg/kg os decreased granulocyte infiltration in zymosan-induced peritonitis in mice.
Dipartimento di Scienze Farmaceutiche, Università di Genova, Genova, Italy. obruno@unige.it
Olga
O
Bruno
Chiara
C
Brullo
Francesco
F
Bondavalli
Silvia
S
Schenone
Susanna
S
Spisani
Maria Sofia
MS
Falzarano
Katia
K
Varani
Elisabetta
E
Barocelli
Vigilio
V
Ballabeni
Carmine
C
Giorgio
Massimiliano
M
Tognolini
D000818:Animals; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D015195:Drug Design; D004952:Esters / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D016209:Interleukin-8 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects*; D011485:Protein Binding; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D004952:Esters; D016209:Interleukin-8; D011720:Pyrazoles; D009240:N-Formylmethionine Leucyl-Phenylalanine; C042932:formylmethionyl-leucyl-phenylalanine methyl ester