Discovery and preclinical studies of (R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-ol (BMS-540215), an in vivo active potent VEGFR-2 inhibitor

被引：125

作者：

Bhide, RS ^{[1
]}

Cai, ZW ^{[1
]}

Zhang, YZ ^{[1
]}

Qian, LG ^{[1
]}

Wei, D ^{[1
]}

Barbosa, S ^{[1
]}

Lombardo, LJ ^{[1
]}

Borzilleri, RM ^{[1
]}

Zheng, XP ^{[1
]}

Wu, LI ^{[1
]}

Barrish, JC ^{[1
]}

Kim, SH ^{[1
]}

Leavitt, K ^{[1
]}

Mathur, A ^{[1
]}

Leith, L ^{[1
]}

Chao, S ^{[1
]}

Wautlet, B ^{[1
]}

Mortillo, S ^{[1
]}

Jeyaseelan, R ^{[1
]}

Kukral, D ^{[1
]}

Hunt, JT ^{[1
]}

Kamath, A ^{[1
]}

Fura, A ^{[1
]}

Vyas, V ^{[1
]}

Marathe, P ^{[1
]}

D'Arienzo, C ^{[1
]}

Derbin, G ^{[1
]}

Fargnoli, J ^{[1
]}

机构：

[1] Bristol Myers Squibb, Pharmaceut Res Inst, Princeton, NJ 08543 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2006年 / 49卷 / 07期

关键词：

D O I：

10.1021/jm051106d

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：2143 / 2146

页数：4

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