title: Synthesis and biological evaluation of N-pyrazolyl-N'-alkyl/benzyl/phenylureas: a new class of potent inhibitors of interleukin 8-induced neutrophil chemotaxis.
abstract: 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.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, University of Genoa, v.le Benedetto XV, 3-Genoa, Italy. obruno@unige.it
authors.forename: Olga
authors.initials: O
authors.lastname: Bruno
authors.forename: Chiara
authors.initials: C
authors.lastname: Brullo
authors.forename: Francesco
authors.initials: F
authors.lastname: Bondavalli
authors.forename: Silvia
authors.initials: S
authors.lastname: Schenone
authors.forename: Angelo
authors.initials: A
authors.lastname: Ranise
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Arduino
authors.forename: Maria B
authors.initials: MB
authors.lastname: Bertolotto
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Montecucco
authors.forename: Luciano
authors.initials: L
authors.lastname: Ottonello
authors.forename: Franco
authors.initials: F
authors.lastname: Dallegri
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Tognolini
authors.forename: Vigilio
authors.initials: V
authors.lastname: Ballabeni
authors.forename: Simona
authors.initials: S
authors.lastname: Bertoni
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Barocelli
mesh_terms: 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
chemical_list: 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