Discovery of 2-{3-[2-(1-Isopropyl-3-methyl-1H-1,2鈥?-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl]-1H-pyrazol-1-yl}-2-methylpropanamide (GDC-0032): A 尾-Sparing

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• 作者：Chudi O. Ndubaku ; Timothy P. Heffron ; Steven T. Staben ; Matthew Baumgardner ; Nicole Blaquiere ; Erin Bradley ; Richard Bull ; Steven Do ; Jennafer Dotson ; Danette Dudley ; Kyle A. Edgar ; Lori S. Friedman ; Richard Goldsmith ; Robert A. Heald ; Aleksandr Kolesnikov ; Leslie Lee ; Cristina Lewis ; Michelle Nannini ; Jim Nonomiya ; Jodie Pang ; Steve Price ; Wei Wei Prior ; Laurent Salphati ; Steve Sideris ; Jeffery J. Wallin ; Lan Wang ; BinQing Wei ; Deepak Sampath ; Alan G. Olivero
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：June 13, 2013
• 年：2013
• 卷：56
• 期：11
• 页码：4597-4610
• 全文大小：667K
• 年卷期：v.56,no.11(June 13, 2013)
• ISSN：1520-4804

文摘

Dysfunctional signaling through the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway leads to uncontrolled tumor proliferation. In the course of the discovery of novel benzoxepin PI3K inhibitors, we observed a strong dependency of in vivo antitumor activity on the free-drug exposure. By lowering the intrinsic clearance, we derived a set of imidazobenzoxazepin compounds that showed improved unbound drug exposure and effectively suppressed growth of tumors in a mouse xenograft model at low drug dose levels. One of these compounds, GDC-0032 (11l), was progressed to clinical trials and is currently under phase I evaluation as a potential treatment for human malignancies.