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

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• 作者：Anthony A. Estrada ; Daniel G. Shore ; Elizabeth Blackwood ; Yung-Hsiang Chen ; Gauri Deshmukh ; Xiao Ding ; Antonio G. DiPasquale ; Jennifer A. Epler ; Lori S. Friedman ; Michael F. T. Koehler ; Lichuan Liu ; Shiva Malek ; Jim Nonomiya ; Daniel F. Ortwine ; Zhonghua Pei ; Steve Sideris ; Frederic St-Jean ; Lan Trinh ; Tom Truong ; Joseph P. Lyssikatos
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：April 11, 2013
• 年：2013
• 卷：56
• 期：7
• 页码：3090-3101
• 全文大小：583K
• 年卷期：v.56,no.7(April 11, 2013)
• ISSN：1520-4804

文摘

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.