1574556-04-9Relevant articles and documents
Selective and potent morpholinone inhibitors of the MDM2-p53 protein-protein interaction
Gonzalez, Ana Z.,Eksterowicz, John,Bartberger, Michael D.,Beck, Hilary P.,Canon, Jude,Chen, Ada,Chow, David,Duquette, Jason,Fox, Brian M.,Fu, Jiasheng,Huang, Xin,Houze, Jonathan B.,Jin, Lixia,Li, Yihong,Li, Zhihong,Ling, Yun,Lo, Mei-Chu,Long, Alexander M.,McGee, Lawrence R.,McIntosh, Joel,McMinn, Dustin L.,Oliner, Jonathan D.,Osgood, Tao,Rew, Yosup,Saiki, Anne Y.,Shaffer, Paul,Wortman, Sarah,Yakowec, Peter,Yan, Xuelei,Ye, Qiuping,Yu, Dongyin,Zhao, Xiaoning,Zhou, Jing,Olson, Steven H.,Medina, Julio C.,Sun, Daqing
, p. 2472 - 2488 (2014/04/17)
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.
