Discovery of AMG 232, a Potent, Selective, and Orally Bioavailable MDM2鈥損53 Inhibitor in Clinical Development

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• 作者：Daqing Sun ; Zhihong Li ; Yosup Rew ; Michael Gribble ; Michael D. Bartberger ; Hilary P. Beck ; Jude Canon ; Ada Chen ; Xiaoqi Chen ; David Chow ; Jeffrey Deignan ; Jason Duquette ; John Eksterowicz ; Benjamin Fisher ; Brian M. Fox ; Jiasheng Fu ; Ana Z. Gonzalez ; Felix Gonzalez-Lopez De Turiso ; Jonathan B. Houze ; Xin Huang ; Min Jiang ; Lixia Jin ; Frank Kayser ; Jiwen (Jim) Liu ; Mei-Chu Lo ; Alexander M. Long ; Brian Lucas ; Lawrence R. McGee ; Joel McIntosh ; Jeff Mihalic ; Jonathan D. Oliner ; Tao Osgood ; Matthew L. Peterson ; Philip Roveto ; Anne Y. Saiki ; Paul Shaffer ; Maria Toteva ; Yingcai Wang ; Yu Chung Wang ; Sarah Wortman ; Peter Yakowec ; Xuelei Yan ; Qiuping Ye ; Dongyin Yu ; Ming Yu ; Xiaoning Zhao ; Jing Zhou ; Jiang Zhu ; Steven H. Olson ; Julio C. Medina
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：February 27, 2014
• 年：2014
• 卷：57
• 期：4
• 页码：1454-1472
• 全文大小：923K
• 年卷期：v.57,no.4(February 27, 2014)
• ISSN：1520-4804

文摘

We recently reported the discovery of AM-8553 (<b>1b>), a potent and selective piperidinone inhibitor of the MDM2鈥損53 interaction. Continued research investigation of the N-alkyl substituent of this series, focused in particular on a previously underutilized interaction in a shallow cleft on the MDM2 surface, led to the discovery of a one-carbon tethered sulfone which gave rise to substantial improvements in biochemical and cellular potency. Further investigation produced AMG 232 (<b>2b>), which is currently being evaluated in human clinical trials for the treatment of cancer. Compound <b>2b> is an extremely potent MDM2 inhibitor (SPR Kb>Db> = 0.045 nM, SJSA-1 EdU ICb>50b> = 9.1 nM), with remarkable pharmacokinetic properties and in vivo antitumor activity in the SJSA-1 osteosarcoma xenograft model (EDb>50b> = 9.1 mg/kg).