| Autor: |
Borzilleri, R. M., Zheng, X., Qian, L., Ellis, C., Cai, Z.-w., Wautlet, B. S., Mortillo, S., Jeyaseelan, R., Sr., Kukral, D. W., Fura, A., Kamath, A., Vyas, V., Tokarski, J. S., Barrish, J. C., Hunt, J. T., Lombardo, L. J., Fargnoli, J., Bhide, R. S. |
| Zdroj: |
Journal of Medicinal Chemistry; June 2005, Vol. 48 Issue: 12 p3991-4008, 18p |
| Abstrakt: |
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. |
| Databáze: |
Supplemental Index |
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