2. Academic Validation
  3. Synthesis and evaluation of 4-anilino-6,7-dialkoxy-3-quinolinecarbonitriles as inhibitors of kinases of the Ras-MAPK signaling cascade

Synthesis and evaluation of 4-anilino-6,7-dialkoxy-3-quinolinecarbonitriles as inhibitors of kinases of the Ras-MAPK signaling cascade

  • Bioorg Med Chem Lett. 2003 Sep 15;13(18):3031-4. doi: 10.1016/s0960-894x(03)00640-1.
Dan Berger 1,  Minu Dutia,  Dennis Powell,  Biqi Wu,  Allan Wissner,  Diane H Boschelli,  M Brawner Floyd,  Nan Zhang,  Nancy Torres,  Jeremy Levin,  Xuemei Du,  Donald Wojciechowicz,  Carolyn Discafani,  Constance Kohler,  Steven C Kim,  Larry R Feldberg,  Karen Collins,  Robert Mallon
Affiliations

Affiliation

  • 1 Chemical Sciences, Wyeth Research, Pearl River, NY 10965, USA. berger@wyeth.com
PMID: 12941327 DOI: 10.1016/s0960-894x(03)00640-1
Abstract

4-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)]anilino-6,7-diethoxy-3-quinolinecarbonitrile (3) was identified as a MEK1 kinase inhibitor with exceptional activity against LoVo cells. The structure-activity relationships of the C-4 aniline substituents were explored, and water-solubilizing groups were added at the C-7 position to improve physical properties. Secondary cellular assays revealed that a compound possessing the appropriate aniline substituents inhibited MEK1 as well as MAPK phosphorylation, thereby acting as a dual inhibitor of the Ras-MAPK signaling cascade.

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