Pyrimidoaminotropanes as Potent, Selective, and Efficacious Small Molecule Kinase Inhibitors of the Mammalian Target of Rapamycin (mTOR)

被引：26

作者：

Estrada, Anthony A. ^{[1
]}

Shore, Daniel G. ^{[1
]}

Blackwood, Elizabeth ^{[2
]}

Chen, Yung-Hsiang ^{[4
]}

Deshmukh, Gauri ^{[4
]}

Ding, Xiao ^{[4
]}

DiPasquale, Antonio G. ^{[5
]}

Epler, Jennifer A. ^{[2
]}

Friedman, Lori S. ^{[2
]}

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

Liu, Lichuan ^{[4
]}

Malek, Shiva ^{[3
]}

Nonomiya, Jim ^{[3
]}

Ortwine, Daniel F. ^{[1
]}

Pei, Zhonghua ^{[1
]}

Sideris, Steve ^{[3
]}

St-Jean, Frederic ^{[1
]}

Trinh, Lan ^{[3
]}

Truong, Tom ^{[2
]}

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 Biochem & Cellular Pharmacol, San Francisco, CA 94080 USA

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

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

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2013年 / 56卷 / 07期

关键词：

ORALLY BIOAVAILABLE INHIBITORS; ATP-COMPETITIVE INHIBITORS; HIGHLY POTENT; IN-VITRO; DISCOVERY; OPTIMIZATION; ACTIVATION; CHEMISTRY; DISTINCT; BEARING;

D O I：

10.1021/jm400194n

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We have recently reported a series of tetrahydroquinazoline (THQ) mTOR inhibitors that produced a clinical candidate 1 (GDC-0349). Through insightful design, we hoped to discover and synthesize a new series of small molecule inhibitors that could attenuate CYP3A4 time-dependent inhibition commonly observed with the THQ scaffold, maintain or improve aqueous solubility and oral absorption, reduce free drug clearance, and selectively increase mTOR potency. Through key in vitro and in vivo studies, we demonstrate that a pyrimidoaminotropane based core was able to address each of these goals. This effort culminated in the discovery of 20 (GNE-555), a highly potent, selective, metabolically stable, and efficacious mTOR inhibitor.

引用

页码：3090 / 3101

页数：12

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