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Artigo Revisado por pares
BIBTEX RIS

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

2011; American Chemical Society; Volume: 55; Issue: 2 Linguagem: Inglês

10.1021/jm201391u

ISSN

1520-4804

Autores

Bassam Abu Thaher, Martina Arnsmann, Frank Totzke, Jan E. Ehlert, Michael H.G. Kubbutat, Christoph Schächtele, Markus O. Zimmermann, Pierre Koch, Frank M. Boeckler, Stefan Laufer,

Tópico(s)

Synthesis and biological activity

Resumo

In the course of searching for new p38α 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 p38α 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.

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