Hit-to-lead optimization of 1,4-dihydroindeno[1,2-c]pyrazoles as a novel class of KDR kinase inhibitors

被引：20

作者：

Dinges, Jurgen

Akritopoulou-Zanze, Irini

Arnold, Lee D.

Barlozzari, Teresa

Bousquet, Peter F.

Cunha, George A.

Ericsson, Anna M.

Iwasaki, Nobuhiko

Michaelides, Michael R.

Ogawa, Nobuo

Phelan, Kathleen M.

Rafferty, Paul

Sowin, Thomas J.

Stewart, Kent D.

Tokuyama, Ryukou

Xia, Zhiren

Zhang, Henry Q.

机构：

[1] Abbott Labs, Global Pharmaceut Res & Dev, Abbott Pk, IL 60064 USA

[2] Abbott Biores Ctr, Worcester, MA 01605 USA

[3] Hokuriku Seiyaku Co Ltd, Fukui 911, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2006年 / 16卷 / 16期

关键词：

cancer; receptor tyrosine kinase; KDR kinase; inhibitor; 1,4-dihydroindeno[1,2-c]pyrazoles;

D O I：

10.1016/j.bmcl.2006.05.052

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of 1,4-dihydroindeno[1,2-c]pyrazoles was prepared and evaluated for their enzymatic inhibition of KDR kinase. Computer modeling studies revealed the importance of attaching a basic side chain in predicting The binding mode of those compounds. Further investigation of structure-activity relationships led to 19, a lead compound with an acceptable selectivity profile, activity in whole cells, and good oral efficacy in an estradiol-induced murine uterine edema model of VEGF activity. (c) 2006 Elsevier Ltd. All rights reserved.

引用

页码：4371 / 4375

页数：5

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