Synthesis and Biological Evaluation of N-Pyrazolyl-N'-alkyl/benzyl/phenylureas: a New Class of Potent Inhibitors of Interleukin 8-Induced Neutrophil Chemotaxis

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• 作者：Olga Bruno ; Chiara Brullo ; Francesco Bondavalli ; Silvia Schenone ; Angelo Ranise ; Nicoletta Arduino ; Maria B. Bertolotto ; Fabrizio Montecucco ; Luciano Ottonello ; Franco Dallegri ; Massimiliano Tognolini
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：July 26, 2007
• 年：2007
• 卷：50
• 期：15
• 页码：3618 - 3626
• 全文大小：184K
• 年卷期：v.50,no.15(July 26, 2007)
• ISSN：1520-4804

文摘

Neutrophils chemotaxis is a complex multistep process that, if upregulated, causes acute inflammation anda 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 activecompounds, 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 thensynthesized to obtain more information for SAR study. Compounds 4a, 4d, and 4k were inactive in thebinding 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, weobserved a complete block of F-actin rise and pseudopod formation.