1-Amino-4-benzylphthalazines as Orally Bioavailable Smoothened Antagonists with Antitumor Activity
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- 作者：Karen Miller-Moslin ; Stefan Peukert ; Rishi K. Jain ; Michael A. McEwan ; Rajesh Karki ; Luis Llamas ; Naeem Yusuff ; Feng He ; Yanhong Li ; Yingchuan Sun ; Miao Dai ; Lawrence Perez ; Walter Michael ; Tao Sheng
- 刊名：Journal of Medicinal Chemistry
- 出版年：2009
- 出版时间：July 9, 2009
- 年：2009
- 卷：52
- 期：13
- 页码：3954-3968
- 全文大小：326K
- 年卷期：v.52,no.13(July 9, 2009)
- ISSN：1520-4804
文摘
Abnormal activation of the Hedgehog (Hh) signaling pathway has been linked to several types of human cancers, and the development of small-molecule inhibitors of this pathway represents a promising route toward novel anticancer therapeutics. A cell-based screen performed in our laboratories identified a new class of Hh pathway inhibitors, 1-amino-4-benzylphthalazines, that act via antagonism of the Smoothened receptor. A variety of analogues were synthesized and their structure−activity relationships determined. This optimization resulted in the discovery of high affinity Smoothened antagonists, one of which was further profiled in vivo. This compound displayed a good pharmacokinetic profile and also afforded tumor regression in a genetic mouse model of medulloblastoma.