Structure-Based Design of Novel Inhibitors of the MDM2鈥損53 Interaction
详细信息 查看全文
- 作者：Yosup Rew ; Daqing Sun ; Felix Gonzalez-Lopez De Turiso ; Michael D. Bartberger ; Hilary P. Beck ; Jude Canon ; Ada Chen ; David Chow ; Jeffrey Deignan ; Brian M. Fox ; Darin Gustin ; Xin Huang ; Min Jiang ; Xianyun Jiao ; Lixia Jin ; Frank Kayser ; David J. Kopecky ; Yihong Li ; Mei-Chu Lo ; Alexander M. Long ; Klaus Michelsen ; Jonathan D. Oliner ; Tao Osgood ; Mark Ragains ; Anne Y. Saiki ; Steve Schneider ; Maria Toteva ; Peter Yakowec ; Xuelei Yan ; Qiuping Ye ; Dongyin Yu ; Xiaoning Zhao ; Jing Zhou ; Julio C. Medina ; Steven H. Olson
- 刊名：Journal of Medicinal Chemistry
- 出版年：2012
- 出版时间：June 14, 2012
- 年：2012
- 卷：55
- 期：11
- 页码：4936-4954
- 全文大小：905K
- 年卷期：v.55,no.11(June 14, 2012)
- ISSN：1520-4804
文摘
Structure-based rational design led to the discovery of novel inhibitors of the MDM2鈥損53 protein鈥損rotein interaction. The affinity of these compounds for MDM2 was improved through conformational control of both the piperidinone ring and the appended N-alkyl substituent. Optimization afforded 29 (AM-8553), a potent and selective MDM2 inhibitor with excellent pharmacokinetic properties and in vivo efficacy.