Design and synthesis of isoquinolines and benzimidazoles as RAF kinase inhibitors

被引：21

作者：

Buchstaller, Hans-Peter ^{[1
]}

Burgdorf, Lars ^{[1
]}

Finsinger, Dirk ^{[1
]}

Stieber, Frank ^{[1
]}

Sirrenberg, Christian ^{[1
]}

Amendt, Christiane ^{[1
]}

Grell, Matthias ^{[1
]}

Zenke, Frank ^{[1
]}

Krier, Mireille ^{[1
]}

机构：

[1] Merck KGaA, Merck Serono, D-64293 Darmstadt, Germany

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2011年 / 21卷 / 08期

关键词：

RAF kinase; Isoquinoline; Benzimidazole; B-RAF; WILD-TYPE; POTENT INHIBITORS; PATHWAY; BRAF; MUTATIONS; DISCOVERY; ACTIVATE;

D O I：

10.1016/j.bmcl.2011.02.108

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

RAF kinase plays a critical role in the RAF-MEK-ERK signaling pathway and inhibitors of RAF could be of use for the treatment of various cancer types. We have designed potent RAF-1 inhibitors bearing novel bicyclic heterocycles as key structural elements for the interaction with the hinge region. In both series exploration of the SAR was focussed on the substitution of the phenyl ring, which binds to the induced fit pocket. Overall, it was confirmed that incorporation of lipophilic substituents was needed for potent Raf inhibition and a number of potent analogues were obtained. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：2264 / 2269

页数：6

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