Potent, Selective, and Orally Bioavailable Inhibitors of Mammalian Target of Rapamycin (mTOR) Kinase Based on a Quaternary Substituted Dihydrofuropyrimidine

被引：26

作者：

Cohen, Frederick ^{[1
]}

Bergeron, Philippe ^{[1
]}

Blackwood, Elizabeth ^{[2
]}

Bowman, Krista K. ^{[3
]}

Chen, Huifen ^{[1
]}

DiPasquale, Antonio G. ^{[7
]}

Epler, Jennifer A. ^{[2
]}

Koehler, Michael F. T. ^{[1
]}

Lau, Kevin ^{[1
]}

Lewis, Cristina ^{[4
]}

Liu, Lichuan ^{[5
]}

Ly, Cuong Q. ^{[1
]}

Malek, Shiva ^{[4
]}

Nonomiya, Jim ^{[4
]}

Ortwine, Daniel F. ^{[1
]}

Pei, Zhonghua ^{[1
]}

Robarge, Kirk D. ^{[1
]}

Sideris, Steve ^{[4
]}

Trinh, Lan ^{[4
]}

Truong, Tom ^{[2
]}

Wu, Jiansheng ^{[6
]}

Zhao, Xianrui ^{[1
]}

Lyssikatos, Joseph P. ^{[1
]}

机构：

[1] Genentech Inc, Dept Discovery Chem, San Francisco, CA 94080 USA

[2] Genentech Inc, Dept Translat Oncol, San Francisco, CA 94080 USA

[3] Genentech Inc, Dept Biol Struct, San Francisco, CA 94080 USA

[4] Genentech Inc, Dept Biochem Pharmacol, San Francisco, CA 94080 USA

[5] Genentech Inc, Dept Drug Metab & Pharmacokinet, San Francisco, CA 94080 USA

[6] Genentech Inc, Dept Prot Chem, San Francisco, CA 94080 USA

[7] Univ Calif Berkeley, Xray Crystallog Facil, Berkeley, CA 94720 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2011年 / 54卷 / 09期

关键词：

D O I：

10.1021/jm200215y

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 K-i < 1.0 nM and were highly (>100x) 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-PD relationship in a mouse model of cancer.

引用

页码：3426 / 3435

页数：10

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