Synthesis and SAR of 1-acetanilide-4-aminopyrazole-substituted quinazolines: Selective inhibitors of Aurora B kinase with potent anti-tumor activity

被引：41

作者：

Foote, Kevin M. ^{[1
]}

Mortlock, Andrew A. ^{[1
]}

Heron, Nicola M. ^{[1
]}

Jung, Frederic H. ^{[2
]}

Hill, George B. ^{[1
]}

Pasquet, Georges ^{[2
]}

Brady, Madeleine C. ^{[1
]}

Green, Stephen ^{[1
]}

Heaton, Simon P. ^{[1
]}

Kearney, Sarah ^{[1
]}

Keen, Nicholas J. ^{[1
]}

Odedra, Rajesh ^{[1
]}

Wedge, Stephen R. ^{[1
]}

Wilkinson, Robert W. ^{[1
]}

机构：

[1] AstraZeneca, Alderley Pk, Macclesfield SK10 4TG, Cheshire, England

[2] AstraZeneca, Ctr Rech, F-51689 Reims 2, France

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 06期

关键词：

Aurora; kinase; quinazoline; pyrazole;

D O I：

10.1016/j.bmcl.2008.02.002

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A new class of 1-acetanilide-4-aminopyrazole-substituted quinazoline Aurora kinase inhibitors has been discovered possessing highly potent cellular activity. Continuous infusion into athymic mice bearing SW620 tumors of the soluble phosphate derivative 2 led to dose-proportional exposure of the des-phosphate compound 8 with a high-unbound fraction. The combination of potent cell activity and high free-drug exposure led to pharmacodynamic changes in the tumor at low doses, indicative of Aurora B-kinase inhibition and a reduction in tumor volume. (C) 2008 Elsevier Ltd. All rights reserved.

引用

页码：1904 / 1909

页数：6

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