title: Identification of pyrrolo[2,1-f][1,2,4]triazine-based inhibitors of Met kinase.
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.
authors.affiliation: Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543-4000, USA. gretchen.schroeder@bms.com
authors.forename: Gretchen M
authors.initials: GM
authors.lastname: Schroeder
authors.forename: Xiao-Tao
authors.initials: XT
authors.lastname: Chen
authors.forename: David K
authors.initials: DK
authors.lastname: Williams
authors.forename: David S
authors.initials: DS
authors.lastname: Nirschl
authors.forename: Zhen-Wei
authors.initials: ZW
authors.lastname: Cai
authors.forename: Donna
authors.initials: D
authors.lastname: Wei
authors.forename: John S
authors.initials: JS
authors.lastname: Tokarski
authors.forename: Yongmi
authors.initials: Y
authors.lastname: An
authors.forename: John
authors.initials: J
authors.lastname: Sack
authors.forename: Zhong
authors.initials: Z
authors.lastname: Chen
authors.forename: Tram
authors.initials: T
authors.lastname: Huynh
authors.forename: Wayne
authors.initials: W
authors.lastname: Vaccaro
authors.forename: Michael
authors.initials: M
authors.lastname: Poss
authors.forename: Barri
authors.initials: B
authors.lastname: Wautlet
authors.forename: Johnni
authors.initials: J
authors.lastname: Gullo-Brown
authors.forename: Kristen
authors.initials: K
authors.lastname: Kellar
authors.forename: Veeraswamy
authors.initials: V
authors.lastname: Manne
authors.forename: John T
authors.initials: JT
authors.lastname: Hunt
authors.forename: Tai W
authors.initials: TW
authors.lastname: Wong
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Lombardo
authors.forename: Joseph
authors.initials: J
authors.lastname: Fargnoli
authors.forename: Robert M
authors.initials: RM
authors.lastname: Borzilleri
mesh_terms: D000818:Animals; D018938:Caco-2 Cells / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D011487:Protein Conformation; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met; D011758:Pyrroles / Q000737:chemistry*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013274:Stomach Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology; D013329:Structure-Activity Relationship; D014227:Triazines / Q000737:chemistry*
chemical_list: D004791:Enzyme Inhibitors; D051638:Ether-A-Go-Go Potassium Channels; C496884:KCNH1 protein, human; D011518:Proto-Oncogene Proteins; D011758:Pyrroles; D017978:Receptors, Growth Factor; D014227:Triazines; D005982:Glutathione Transferase; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases