Structure-guided identification of novel VEGFR-2 kinase inhibitors via solution phase parallel synthesis

被引：102

作者：

Tripathy, R ^{[1
]}

Reiboldt, A ^{[1
]}

Messina, PA ^{[1
]}

Iqbal, M ^{[1
]}

Singh, J ^{[1
]}

Bacon, ER ^{[1
]}

Angeles, TS ^{[1
]}

Yang, SX ^{[1
]}

Albom, MS ^{[1
]}

Robinson, C ^{[1
]}

Chang, H ^{[1
]}

Ruggeri, BA ^{[1
]}

Mallamo, JP ^{[1
]}

机构：

[1] CephalonInc, Discovery Res, W Chester, PA 19380 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2006年 / 16卷 / 08期

关键词：

VEGFR-2; kinase; inhibitors; pyrazolones; oxindole; anti-tumor; angiogenesis; Knoevenagel condensation; solution phase parallel synthesis;

D O I：

10.1016/j.bmcl.2006.01.063

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Structural analysis of the essential binding elements of the oxindole-based kinase inhibitor (1) led to the identification of a novel class of heterocyclic-substituted pyrazolones. Knoevenagel condensation of a variety of activated methylene nucleophiles with indole or pyrrole carboxaldehydes provided a focused library of molecules, each containing elements of kinase pharmacophore probe. Initial screening for VEGFR-2 kinase inhibit ion eliminated several of the probes. Identification of ail active pyrazolone motif and further optimization resulted in several highly potent VEGFR-2 inhibitors with cellular efficacy, anti-angiogenic activity ex vivo in rat aortic ring explant cultures, and oral anti-tumor efficacy in nude mice. (C) 2006 Elsevier Ltd. All rights reserved.

引用

页码：2158 / 2162

页数：5

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