Selective and Potent Morpholinone Inhibitors of the MDM2鈥損53 Protein鈥揚rotein Interaction

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• 作者：Ana Z. Gonzalez ; John Eksterowicz ; Michael D. Bartberger ; Hilary P. Beck ; Jude Canon ; Ada Chen ; David Chow ; Jason Duquette ; Brian M. Fox ; Jiasheng Fu ; Xin Huang ; Jonathan B. Houze ; Lixia Jin ; Yihong Li ; Zhihong Li ; Yun Ling ; Mei-Chu Lo ; Alexander M. Long ; Lawrence R. McGee ; Joel McIntosh ; Dustin L. McMinn ; Jonathan D. Oliner ; Tao Osgood ; Yosup Rew ; Anne Y. Saiki ; Paul Shaffer ; Sarah Wortman ; Peter Yakowec ; Xuelei Yan ; Qiuping Ye ; Dongyin Yu ; Xiaoning Zhao ; Jing Zhou ; Steven H. Olson ; Julio C. Medina ; Daqing Sun
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：March 27, 2014
• 年：2014
• 卷：57
• 期：6
• 页码：2472-2488
• 全文大小：831K
• 年卷期：v.57,no.6(March 27, 2014)
• ISSN：1520-4804

文摘

We previously reported the discovery of AMG 232, a highly potent and selective piperidinone inhibitor of the MDM2鈥損53 interaction. Our continued search for potent and diverse analogues led to the discovery of novel morpholinone MDM2 inhibitors. This change to a morpholinone core has a significant impact on both potency and metabolic stability compared to the piperidinone series. Within this morpholinone series, AM-8735 emerged as an inhibitor with remarkable biochemical potency (HTRF IC₅₀ = 0.4 nM) and cellular potency (SJSA-1 EdU IC₅₀ = 25 nM), as well as pharmacokinetic properties. Compound 4 also shows excellent antitumor activity in the SJSA-1 osteosarcoma xenograft model with an ED₅₀ of 41 mg/kg. Lead optimization toward the discovery of this inhibitor as well as key differences between the morpholinone and the piperidinone series will be described herein.