658085-65-5Relevant articles and documents
Design, synthesis, and evaluation of orally active 4-(2,4-difluoro-5- (methoxycarbamoyl)phenylamino)pyrrolo[2,1-f][1,2,4]triazines as dual vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1 inhibitors
Borzilleri, Robert M.,Zheng, Xiaoping,Qian, Ligang,Ellis, Christopher,Cai, Zhen-Wei,Wautlet, Barri S.,Mortillo, Steve,Jeyaseelan Sr., Robert,Kukral, Daniel W.,Fura, Aberra,Kamath, Amrita,Vyas, Viral,Tokarski, John S.,Barrish, Joel C.,Hunt, John T.,Lombardo, Louis J.,Fargnoli, Joseph,Bhide, Rajeev S.
, p. 3991 - 4008 (2005)
A series of substituted 4-(2,4-difluoro-5-(methoxycarbamoyl)phenylamino) pyrrolo[2,1-f][1,2,4]-triazines was identified as potent and selective inhibitors of the tyrosine kinase activity of the growth factor receptors VEGFR-2 (Flk-1, KDR) and FGFR-1. The enzyme kinetics associated with the VEGFR-2 inhibition of compound 50 (Ki = 52 ± 3 nM) confirmed that the pyrrolo-[2,1-f][1,2,4]triazine analogues are competitive with ATP. Several analogues demonstrated low-nanomolar inhibition of VEGF- and FGF-dependent human umbilical vein endothelial cell (HUVEC) proliferation. Replacement of the C6-ester substituent of the pyrrolo[2,1-f][1,2,4]-triazine core with heterocyclic bioisosteres, such as substituted 1,3,5-oxadiazoles, afforded compounds with excellent oral bioavailability in mice (i.e., 50 Fpo = 79%). Significant antitumor efficacy was observed with compounds 44, 49, and 50 against established L2987 human lung carcinoma xenografts implanted in athymic mice. A full account of the synthesis, structure-activity relationships, pharmacology, and pharmacokinetic properties of analogues within the series is presented.
