Identification of pyrrolo[2,1-f][1,2,4]triazine-based inhibitors of Met kinase |
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Authors: | Schroeder Gretchen M Chen Xiao-Tao Williams David K Nirschl David S Cai Zhen-Wei Wei Donna Tokarski John S An Yongmi Sack John Chen Zhong Huynh Tram Vaccaro Wayne Poss Michael Wautlet Barri Gullo-Brown Johnni Kellar Kristen Manne Veeraswamy Hunt John T Wong Tai W Lombardo Louis J Fargnoli Joseph Borzilleri Robert M |
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Affiliation: | Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543-4000, USA. gretchen.schroeder@bms.com |
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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. |
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