期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 49, 期 7, 页码 2143-2146出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm051106d
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A series of substituted 4-(4-fluoro-1H-indol-5-yloxy)pyrrolo-[2,1-f][1,2,4]triazine-based inhibitors of vascular endothelial growth factor receptor-2 kinase is reported. Structure-activity relationship studies revealed that a methyl group at the 5-position and a Substituted alkoxy group at the 6-position of the pyrrolo[2, 1-f][ 1,2,4]triazine core gave potent compounds. Biochemical potency, kinase selectivity, and pharmacokinetics of the series were optimized and in vitro safety liabilities were minimized to afford BMS-540215 (12). which demonstrated robust preclinical in vivo activity in human tumor xenograft models. The L-alanine prodrug of 12, BMS-582664 (21), is currently under evaluation in clinical trials for the treatment of solid tumors.
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