The design, synthesis, and biological evaluation of potent receptor tyrosine kinase inhibitors

被引：24

作者：

Kim, Moon H. ^{[1
]}

Tsuhako, Amy Lew ^{[1
]}

Co, Erick W. ^{[1
]}

Aftab, Dana T. ^{[1
]}

Bentzien, Frauke ^{[1
]}

Chen, Jason ^{[1
]}

Cheng, Wei ^{[1
]}

Engst, Stefan ^{[1
]}

Goon, Levina ^{[1
]}

Klein, Rhett R. ^{[1
]}

Le, Donna T. ^{[1
]}

Mac, Morrison ^{[1
]}

Parks, Jason J. ^{[1
]}

Qian, Fawn ^{[1
]}

Rodriquez, Monica ^{[1
]}

Stout, Thomas J. ^{[1
]}

Till, Jeffrey H. ^{[1
]}

Won, Kwang-Ai ^{[1
]}

Wu, Xiang ^{[1
]}

Yakes, F. Michael ^{[1
]}

Yu, Peiwen ^{[1
]}

Zhang, Wentao ^{[1
]}

Zhao, Yeping ^{[1
]}

Lamb, Peter ^{[1
]}

Nuss, John M. ^{[1
]}

Xu, Wei ^{[1
]}

机构：

[1] Exelixis, San Francisco, CA 94080 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2012年 / 22卷 / 15期

关键词：

Receptor tyrosine kinase; Angiogenesis; KDR; VEGFR; Flt; FGFR; PDGFR; Oxindole; Indolin-2-one; GROWTH-FACTOR RECEPTOR; VEGF; ANTIANGIOGENESIS; INDOLIN-2-ONES; IDENTIFICATION; RESISTANCE; AG-013736; AGENT;

D O I：

10.1016/j.bmcl.2012.06.029

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Variously substituted indolin-2-ones were synthesized and evaluated for activity against KDR, Flt-1, FGFR-1 and PDGFR. Extension at the 5-position of the oxindole ring with ethyl piperidine (compound 7i) proved to be the most beneficial for attaining both biochemical and cellular potencies. Further optimization of 7i to balance biochemical and cellular potencies with favorable ADME/ PK properties led to the identification of 8h, a compound with a clean CYP profile, acceptable pharmacokinetic and toxicity profiles, and robust efficacy in multiple xenograft tumor models. (c) 2012 Elsevier Ltd. All rights reserved.

引用

页码：4979 / 4985

页数：7

共 35 条

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