| Literature DB >> 23597064 |
Felix Gonzalez-Lopez de Turiso1, Daqing Sun, Yosup Rew, Michael D Bartberger, Hilary P Beck, Jude Canon, Ada Chen, David Chow, Tiffany L Correll, Xin Huang, Lisa D Julian, Frank Kayser, Mei-Chu Lo, Alexander M Long, Dustin McMinn, Jonathan D Oliner, Tao Osgood, Jay P Powers, Anne Y Saiki, Steve Schneider, Paul Shaffer, Shou-Hua Xiao, Peter Yakowec, Xuelei Yan, Qiuping Ye, Dongyin Yu, Xiaoning Zhao, Jing Zhou, Julio C Medina, Steven H Olson.
Abstract
Structural analysis of both the MDM2-p53 protein-protein interaction and several small molecules bound to MDM2 led to the design and synthesis of tetrasubstituted morpholinone 10, an MDM2 inhibitor with a biochemical IC50 of 1.0 μM. The cocrystal structure of 10 with MDM2 inspired two independent optimization strategies and resulted in the discovery of morpholinones 16 and 27 possessing distinct binding modes. Both analogues were potent MDM2 inhibitors in biochemical and cellular assays, and morpholinone 27 (IC50 = 0.10 μM) also displayed suitable PK profile for in vivo animal experiments. A pharmacodynamic (PD) experiment in mice implanted with human SJSA-1 tumors showed p21(WAF1) mRNA induction (2.7-fold over vehicle) upon oral dosing of 27 at 300 mg/kg.Entities:
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Year: 2013 PMID： 23597064 DOI： 10.1021/jm400293z
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446