- Pyrrolotriazine inhibitors of kinases
-
The present invention provides compounds of formula I and pharmaceutically acceptable salts thereof. The formula I compounds inhibit the tyrosine kinase activity of growth factor receptors such as VEGFR-2, FGFR-1, PDGFR, HER-1, HER-2, thereby making them useful as anti-cancer agents. The formula I compounds are also useful for the treatment of other diseases associated with signal transduction pathways operating through growth factor receptors.
- -
-
Page/Page column 24
(2008/06/13)
-
- Discovery of the pyrrolo[2,1-f][1,2,4]triazine nucleus as a new kinase inhibitor template
-
The pyrrolo[2,1-f][1,2,4]triazine nucleus was identified as a novel kinase inhibitor template which effectively mimics the well-known quinazoline kinase inhibitor scaffold. Attachment of a 4-((3-chloro-4-fluorophenyl)amino) substituent to the template provided potent biochemical inhibitors of the tyrosine kinase activity of EGFR, as well as inhibition of cellular proliferation of the human colon tumor cell line DiFi. Attachment of a 4-((3-hydroxy-4-methylphenyl)amino) substituent provided potent inhibitors of VEGFR-2 which also showed effects on the VEGF-dependent proliferation of human umbilical vein endothelial cells. Biological activity was maintained with substitution at positions 5 or 6, but not 7, suggesting that the former positions are promising sites for introducing side chains which modulate physicochemical. properties. Preliminary inhibition studies with varying ATP concentrations suggest that, like the quinazoline-based kinase inhibitors, the pyrrolotriazine-based inhibitors bind in the ATP pocket.
- Hunt, John T.,Mitt, Toomas,Borzilleri, Robert,Gullo-Brown, Johnni,Fargnoli, Joseph,Fink, Brian,Han, Wen-Ching,Mortillo, Steven,Vite, Gregory,Wautlet, Barri,Wong, Tai,Yu, Chiang,Zheng, Xiaoping,Bhide, Rajeev
-
p. 4054 - 4059
(2007/10/03)
-