Tri- and Tetrasubstituted Pyrazole Derivates: Regioisomerism Switches Activity from p38MAP Kinase to Important Cancer Kinases

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• 作者：Bassam Abu Thaher ; Martina Arnsmann ; Frank Totzke ; Jan E. Ehlert ; Michael H. G. Kubbutat ; Christoph Sch盲chtele ; Markus O. Zimmermann ; Pierre Koch ; Frank M. Boeckler ; Stefan A. Laufer
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：January 26, 2012
• 年：2012
• 卷：55
• 期：2
• 页码：961-965
• 全文大小：313K
• 年卷期：v.55,no.2(January 26, 2012)
• ISSN：1520-4804

文摘

In the course of searching for new p38伪 MAP kinase inhibitors, we found that the regioisomeric switch from 3-(4-fluorophenyl)-4-(pyridin-4-yl)-1-(aryl)-1H-pyrazol-5-amine to 4-(4-fluorophenyl)-3-(pyridin-4-yl)-1-(aryl)-1H-pyrazol-5-amine led to an almost complete loss of p38伪 inhibition, but they showed activity against important cancer kinases. Among the tested derivatives, 4-(4-fluorophenyl)-3-(pyridin-4-yl)-1-(2,4,6-trichlorophenyl)-1H-pyrazol-5-amine (6a) exhibited the best activity, with IC₅₀ in the nanomolar range against Src, B-Raf wt, B-Raf V600E, EGFRs, and VEGFR-2, making it a good lead for novel anticancer programs.