Design and Optimization of Potent and Orally Bioavailable Tetrahydronaphthalene Raf Inhibitors
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- 作者：Alexandra E. Gould ; Ruth Adams ; Sharmila Adhikari ; Kathleen Aertgeerts ; Roushan Afroze ; Christopher Blackburn ; Emily F. Calderwood ; Ryan Chau ; Jouhara Chouitar ; Matthew O. Duffey ; Dylan B. England ; Cheryl Farrer ; Nancy Forsyth ; Khristofer Garcia ; Jeffery Gaulin ; Paul D. Greenspan ; Ribo Guo ; Sean J. Harrison ; Shih-Chung Huang ; Natalia Iartchouk ; Dave Janowick ; Mi-Sook Kim ; Bheemashankar Kulkarni ; Steven P. Langston ; Jane X. Liu ; Li-Ting Ma ; Saurabh Menon ; Hirotake Mizutani ; Erin Paske ; Christelle C. Renou ; Mansoureh Rezaei ; R. Scott Rowland ; Michael D. Sintchak ; Michael D. Smith ; Stephen G. Stroud ; Ming Tregay ; Yuan Tian ; Ole P. Veiby ; Tricia J. Vos ; Stepan Vyskocil ; Juliet Williams ; Tianlin Xu ; Johnny J. Yang ; Jason Yano ; Hongbo Zeng ; Dong Mei Zhang ; Qin Zhang ; Katherine M. Galvin
- 刊名：Journal of Medicinal Chemistry
- 出版年：2011
- 出版时间：March 24, 2011
- 年：2011
- 卷：54
- 期：6
- 页码：1836-1846
- 全文大小：1021K
- 年卷期：v.54,no.6(March 24, 2011)
- ISSN：1520-4804
文摘
Inhibition of mutant B-Raf signaling, through either direct inhibition of the enzyme or inhibition of MEK, the direct substrate of Raf, has been demonstrated preclinically to inhibit tumor growth. Very recently, treatment of B-Raf mutant melanoma patients with a selective B-Raf inhibitor has resulted in promising preliminary evidence of antitumor activity. This article describes the design and optimization of tetrahydronaphthalene-derived compounds as potent inhibitors of the Raf pathway in vitro and in vivo. These compounds possess good pharmacokinetic properties in rodents and inhibit B-Raf mutant tumor growth in mouse xenograft models.