Selective Inhibitors of the Mutant B-Raf Pathway: Discovery of a Potent and Orally Bioavailable Aminoisoquinoline

详细信息    查看全文

• 作者：Adrian L. Smith ; Frenel F. DeMorin ; Nick A. Paras ; Qi Huang ; Jeffrey K. Petkus ; Elizabeth M. Doherty ; Thomas Nixey ; Joseph L. Kim ; Douglas A. Whittington ; Linda F. Epstein ; Matthew R. Lee ; Mark J. Ros
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：October 22, 2009
• 年：2009
• 卷：52
• 期：20
• 页码：6189-6192
• 全文大小：809K
• 年卷期：v.52,no.20(October 22, 2009)
• ISSN：1520-4804

文摘

The discovery and optimization of a novel series of aminoisoquinolines as potent, selective, and efficacious inhibitors of the mutant B-Raf pathway is presented. The N-linked pyridylpyrimidine benzamide 2 was identified as a potent, modestly selective inhibitor of the B-Raf enzyme. Replacement of the benzamide with an aminoisoquinoline core significantly improved kinase selectivity and imparted favorable pharmacokinetic properties, leading to the identification of 1 as a potent antitumor agent in xenograft models.