Discovery of AMG 232, a Potent, Selective, and Orally Bioavailable MDM2-p53 Inhibitor in Clinical Development

作者：Sun Daqing^*; Li Zhihong; Rew Yosup; Gribble Michael; Bartberger Michael D; Beck Hilary P; Canon Jude; Chen Ada; Chen Xiaoqi; Chow David; Deignan Jeffrey; Duquette Jason; Eksterowicz John; Fisher Benjamin; Fox Brian M; Fu Jiasheng; Gonzalez Ana Z; De Turiso Felix Gonzalez Lopez; Houze Jonathan B; Huang Xin; Jiang Min; Jin Lixia; Kayser Frank; Liu Jiwen; Lo Mei Chu; Long Alexander M; Lucas Brian; McGee Lawrence R; McIntosh Joel; Mihalic Jeff

来源：Journal of Medicinal Chemistry, 2014, 57(4): 1454-1472.

DOI：10.1021/jm401753e

We recently reported the discovery of AM-8553 (1), a potent and selective piperidinone inhibitor of the MDM2-p53 interaction. Continued research investigation of the N-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 (2), which is currently being evaluated in human clinical trials for the treatment of cancer. Compound 2 is an extremely potent MDM2 inhibitor (SPR K-D = 0.045 nM, SJSA-1 EdU IC50 = 9.1 nM), with remarkable pharmacokinetic properties and in vivo antitumor activity in the SJSA-1 osteosarcoma xenograft model (ED50 = 9.1 mg/kg).

• 出版日期2014-2-27