Synthesis and biological evaluation of N-pyrazolyl-N'-alkyl/benzyl/phenylureas: a new class of potent inhibitors of interleukin 8-induced neutrophil chemotaxis.
Neutrophils chemotaxis is a complex multistep process that, if upregulated, causes acute inflammation and a number of autoimmune diseases. We report here the synthesis of a new N-(4-substituted)pyrazolyl-N'-alkyl/benzyl/phenylureas that are potent inhibitors of interleukin-8 (IL8)-induced neutrophil chemotaxis. The first series of compounds, obtained by functionalization with a urea moiety of the 5-amino-1-(2-hydroxy-2-phenylethyl)-1H-pyrazole-4-carboxylic acid ethyl ester 3, blocked the IL8-induced neutrophil chemotaxis, while they did not block N-formylmethionylleucylphenylalanine-mediated chemotaxis. The most active compounds, 3-benzyl- (4d), 3-(4-benzylpiperazinyl)- (4i), 3-phenyl- (4k) and 3-isopropylureido (4a) derivatives, showed an IC50 of 10, 14, 45, and 55 nM, respectively. Several different molecules were then synthesized to obtain more information for SAR study. Compounds 4a, 4d, and 4k were inactive in the binding assays on CXCR1 and CXCR2 (IL8 receptors), whereas they inhibited the phosphorylation of PTKs (protein tyrosine kinases) in the 50-70 kDa region. Moreover, in the presence of the same derivatives, we observed a complete block of F-actin rise and pseudopod formation.
Bruno
Olga
O
Dipartimento di Scienze Farmaceutiche, University of Genoa, v.le Benedetto XV, 3-Genoa, Italy. obruno@unige.it
Brullo
Chiara
C
Bondavalli
Francesco
F
Schenone
Silvia
S
Ranise
Angelo
A
Arduino
Nicoletta
N
Bertolotto
Maria B
MB
Montecucco
Fabrizio
F
Ottonello
Luciano
L
Dallegri
Franco
F
Tognolini
Massimiliano
M
Ballabeni
Vigilio
V
Bertoni
Simona
S
Barocelli
Elisabetta
E
D000199:Actins / Q000037:antagonists & inhibitors; D000328:Adult; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte; D006801:Humans; D016209:Interleukin-8 / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology; D010529:Peritoneal Cavity / Q000166:cytology; D010538:Peritonitis / Q000473:pathology / Q000517:prevention & control; D010671:Phenylurea Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011554:Pseudopodia / Q000187:drug effects / Q000502:physiology; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D023062:Receptors, Interleukin-8A / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000378:metabolism; D013329:Structure-Activity Relationship
D000199:Actins; D000893:Anti-Inflammatory Agents; D016209:Interleukin-8; D010671:Phenylurea Compounds; D011720:Pyrazoles; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D009240:N-Formylmethionine Leucyl-Phenylalanine; D051057:Proto-Oncogene Proteins c-akt