Document Detail

Discovery of AM-7209, a Potent and Selective 4-Amidobenzoic Acid Inhibitor of the MDM2-p53 Interaction.
MedLine Citation:
PMID:  25384157     Owner:  NLM     Status:  Publisher    
Structure-based rational design and extensive SAR led to the discovery of AMG 232 (1), a potent piperidinone inhibitor of 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 an 4-amidobenzoic acid, afforded AM-7209 (25), featuring improved potency (KD from ITC competition = 38 pM, SJSA-1 EdU IC50 = 1.6 nM), remarkable pharmacokinetic properties, and in vivo anti-tumor 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.
Yosup Rew; Daqing Sun; Xuelei Yan; Hilary Plake Beck; Jude Canon; Chen Ada; Jason Duquette; John Eksterowicz; Brian M Fox; Jiasheng Fu; Ana Z Gonzalez; Jonathan B Houze; Xin Huang; Ben Jiang; Lixia Jin; Yihong Li; Zhihong Li; Yun Ling; Mei-Chu Lo; Alexander M Long; Lawrence R McGee; Joel McIntosh; Jon Oliner; Tao Osgood; Anne Saiki; Paul Shaffer; Sarah Wortman; Peter Yakowec; Qiuping Ye; Dongyin Yu; Julio C Medina; Steven H Olson
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-11-10
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  -     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2014 Nov 
Date Detail:
Created Date:  2014-11-10     Completed Date:  -     Revised Date:  2014-11-11    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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