| Literature DB >> 24548297 |
Ana Z Gonzalez1, 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.
Abstract
We previously reported the discovery of AMG 232, a highly potent and selective piperidinone inhibitor of the MDM2-p53 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.Entities:
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Year: 2014 PMID： 24548297 DOI： 10.1021/jm401767k
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446