Identification of pyrrolo[2,1-f][1,2,4]triazine-based inhibitors of Met kinase
- 作者：Gretchen M. Schroeder ; Xiao-Tao Chen ; David K. Williams ; David S. Nirschl ; Zhen-Wei Cai ; Donna Wei ; John S. Tokarski ; Yongmi An ; John Sack ; Zhong Chen ; Tram Huynh ; Wayne Vaccaro ; Michael Poss ; Barri W
- 关键词：Met kinase ; Hepatocyte growth factor receptor ; HGFR ; Pyrrolotriazine ; Gastric carcinoma
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2008
- 期刊代码：10_0960894x
- 类别：ch
- 出版时间：15 March 2008
- 卷：18
- 期：6
- 页码：1945-1951
- 文件大小：296 K
摘要
An amide library derived from the pyrrolo[2,1-f][1,2,4]triazine scaffold led to the identification of modest inhibitors of Met kinase activity. Introduction of polar side chains at C-6 of the pyrrolotriazine core provided significant improvements in in vitro potency. The amide moiety could be replaced with acylurea and malonamide substituents to give compounds with improved potency in the Met-driven GTL-16 human gastric carcinoma cell line. Acylurea pyrrolotriazines with substitution at C-5 demonstrated single digit nanomolar kinase activity. X-ray crystallography revealed that the C-5 substituted pyrrolotriazines bind to the Met kinase domain in an ATP-competitive manner.