Optimization of tetrahydronaphthalene inhibitors of Raf with selectivity over hERG
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- 作者：Shih-Chung Huang ; Sharmila Adhikari ; Roushan Afroze ; Katherine Brewer ; Emily F. Calderwood ; Jouhara Chouitar ; Dylan B. England ; Craig Fisher ; Katherine M. Galvin ; Jeffery Gaulin ; Paul D. Greenspan ; Sean J. Harrison ; Mi-Sook Kim ; Steven P. Langston ; Li-Ting Ma ; Saurabh Menon ; Hirotake Mizutani ; Mansoureh Rezaei ; Michael D. Smith ; Dong Mei Zhang ; Alexandra E. Gould
- 关键词：B-Raf ; B-Raf inhibitor ; hERG
- 刊名：Bioorganic & Medicinal Chemistry Letters
- 出版年：2016
- 出版时间：15 February 2016
- 年：2016
- 卷：26
- 期：4
- 页码：1156-1160
- 全文大小：1865 K
文摘
Investigations of a biaryl ether scaffold identified tetrahydronaphthalene Raf inhibitors with good in vivo activity; however these compounds had affinity toward the hERG potassium channel. Herein we describe our work to eliminate this hERG activity via alteration of the substituents on the benzoic amide functionality. The resulting compounds have improved selectivity against the hERG channel, good pharmacokinetic properties and potently inhibit the Raf pathway in vivo.