Discovery of AMG 232, a Potent, Selective, and Orally Bioavailable MDM2–p53 Inhibitor in Clinical Development Daqing Sun Zhihong Li Yosup Rew Michael Gribble Michael D. Bartberger Hilary P. Beck Jude Canon Ada Chen Xiaoqi Chen David Chow Jeffrey Deignan Jason Duquette John Eksterowicz Benjamin Fisher Brian M. Fox Jiasheng Fu Ana Z. Gonzalez Felix Gonzalez-Lopez De Turiso Jonathan B. Houze Xin Huang Min Jiang Lixia Jin Frank Kayser Jiwen (Jim) Liu Mei-Chu Lo Alexander M. Long Brian Lucas Lawrence R. McGee Joel McIntosh Jeff Mihalic Jonathan D. Oliner Tao Osgood Matthew L. Peterson Philip Roveto Anne Y. Saiki Paul Shaffer Maria Toteva Yingcai Wang Yu Chung Wang Sarah Wortman Peter Yakowec Xuelei Yan Qiuping Ye Dongyin Yu Ming Yu Xiaoning Zhao Jing Zhou Jiang Zhu Steven H. Olson Julio C. Medina 10.1021/jm401753e.s001 https://acs.figshare.com/articles/journal_contribution/Discovery_of_AMG_232_a_Potent_Selective_and_Orally_Bioavailable_MDM2_p53_Inhibitor_in_Clinical_Development/2319247 We recently reported the discovery of AM-8553 (<b>1</b>), a potent and selective piperidinone inhibitor of the MDM2–p53 interaction. Continued research investigation of the <i>N</i>-alkyl substituent of this series, focused in particular on a previously underutilized interaction in a shallow cleft on the MDM2 surface, led to the discovery of a one-carbon tethered sulfone which gave rise to substantial improvements in biochemical and cellular potency. Further investigation produced AMG 232 (<b>2</b>), which is currently being evaluated in human clinical trials for the treatment of cancer. Compound <b>2</b> is an extremely potent MDM2 inhibitor (SPR <i>K</i><sub>D</sub> = 0.045 nM, SJSA-1 EdU IC<sub>50</sub> = 9.1 nM), with remarkable pharmacokinetic properties and in vivo antitumor activity in the SJSA-1 osteosarcoma xenograft model (ED<sub>50</sub> = 9.1 mg/kg). 2014-02-27 00:00:00 0.045 nM SPR KD Clinical DevelopmentWe SJSA EdU IC 50 osteosarcoma xenograft model AMG pharmacokinetic properties 9.1 ED 50 MDM 2 surface research investigation AM MDM 2 inhibitor piperidinone inhibitor interaction vivo antitumor activity Compound 2