| Literature DB >> 18289854 |
Gretchen M Schroeder1, 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 Wautlet, Johnni Gullo-Brown, Kristen Kellar, Veeraswamy Manne, John T Hunt, Tai W Wong, Louis J Lombardo, Joseph Fargnoli, Robert M Borzilleri.
Abstract
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.Entities:
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Year: 2008 PMID： 18289854 DOI： 10.1016/j.bmcl.2008.01.121
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823