Potent, Selective, and Orally Bioavailable Inhibitors of Mammalian Target of Rapamycin (mTOR) Kinase Based on a Quaternary Substituted Dihydrofuropyrimidine
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- 作者：Frederick Cohen ; Philippe Bergeron ; Elizabeth Blackwood ; Krista K. Bowman ; Huifen Chen ; Antonio G. DiPasquale ; Jennifer A. Epler ; Michael F. T. Koehler ; Kevin Lau ; Cristina Lewis ; Lichuan Liu ; Cuong Q. Ly ; Shiva Malek ; Jim Nonomiya ; Daniel F. Ortwine ; Zhonghua Pei ; Kirk D. Robarge ; Steve Sideris ; Lan Trinh ; Tom Truong ; Jiansheng Wu ; Xianrui Zhao ; Joseph P. Lyssikatos
- 刊名：Journal of Medicinal Chemistry
- 出版年：2011
- 出版时间：May 12, 2011
- 年：2011
- 卷：54
- 期：9
- 页码：3426-3435
- 全文大小：1082K
- 年卷期：v.54,no.9(May 12, 2011)
- ISSN：1520-4804
文摘
A series of inhibitors of mTOR kinase based on a quaternary-substituted dihydrofuropyrimidine was designed and synthesized. The most potent compounds in this series inhibited mTOR kinase with Ki < 1.0 nM and were highly (>100脳) selective for mTOR over the closely related PI3 kinases. Compounds in this series showed inhibition of the pathway and antiproliferative activity in cell-based assays. Furthermore, these compounds had excellent mouse PK, and showed a robust PK鈭扨D relationship in a mouse model of cancer.