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 (1), 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 (2), which is currently being evaluated in human clinical trials for the treatment of cancer. Compound 2 is an extremely potent MDM2 inhibitor (SPR K_D = 0.045 nM, SJSA-1 EdU IC₅₀ = 9.1 nM), with remarkable pharmacokinetic properties and in vivo antitumor activity in the SJSA-1 osteosarcoma xenograft model (ED₅₀ = 9.1 mg/kg).