| Literature DB >> 25384157 |
Yosup Rew1, Daqing Sun, Xuelei Yan, Hilary P Beck, Jude Canon, Ada Chen, Jason Duquette, John Eksterowicz, Brian M Fox, Jiasheng Fu, Ana Z Gonzalez, Jonathan Houze, Xin Huang, Min Jiang, Lixia Jin, Yihong Li, Zhihong Li, Yun Ling, Mei-Chu Lo, Alexander M Long, Lawrence R McGee, Joel McIntosh, Jonathan D Oliner, Tao Osgood, Anne Y Saiki, Paul Shaffer, Yu Chung Wang, Sarah Wortman, Peter Yakowec, Qiuping Ye, Dongyin Yu, Xiaoning Zhao, Jing Zhou, Julio C Medina, Steven H Olson.
Abstract
Structure-based rational design and extensive structure-activity relationship studies led to the discovery of AMG 232 (1), a potent piperidinone inhibitor of the MDM2-p53 association, which is currently being evaluated in human clinical trials for the treatment of cancer. Further modifications of 1, including replacing the carboxylic acid with a 4-amidobenzoic acid, afforded AM-7209 (25), featuring improved potency (KD from ITC competition was 38 pM, SJSA-1 EdU IC50 = 1.6 nM), remarkable pharmacokinetic properties, and in vivo antitumor activity in both the SJSA-1 osteosarcoma xenograft model (ED50 = 2.6 mg/kg QD) and the HCT-116 colorectal carcinoma xenograft model (ED50 = 10 mg/kg QD). In addition, 25 possesses distinct mechanisms of elimination compared to 1.Entities:
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Year: 2014 PMID： 25384157 DOI： 10.1021/jm501550p
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446