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Identification of pyrrolo[2,1-f][1,2,4]triazine-based inhibitors of Met kinase.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2008 Mar 15; Vol. 18 (6), pp. 1945-51. Date of Electronic Publication: 2008 Feb 07. - Publication Year :
- 2008
-
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.
- Subjects :
- Animals
Caco-2 Cells drug effects
Cell Proliferation drug effects
Cells, Cultured drug effects
Crystallography, X-Ray
Enzyme Inhibitors chemical synthesis
Enzyme Inhibitors pharmacokinetics
Ether-A-Go-Go Potassium Channels antagonists & inhibitors
Glutathione Transferase antagonists & inhibitors
Hepatocytes drug effects
Hepatocytes metabolism
Humans
Mice
Microsomes, Liver drug effects
Microsomes, Liver metabolism
Molecular Structure
Protein Conformation
Proto-Oncogene Proteins metabolism
Proto-Oncogene Proteins c-met
Receptor Protein-Tyrosine Kinases metabolism
Receptors, Growth Factor metabolism
Stomach Neoplasms blood
Stomach Neoplasms enzymology
Structure-Activity Relationship
Enzyme Inhibitors pharmacology
Proto-Oncogene Proteins antagonists & inhibitors
Pyrroles chemistry
Receptor Protein-Tyrosine Kinases antagonists & inhibitors
Receptors, Growth Factor antagonists & inhibitors
Stomach Neoplasms drug therapy
Triazines chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 18
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 18289854
- Full Text :
- https://doi.org/10.1016/j.bmcl.2008.01.121