Discovery, Synthesis, and Biological Evaluation of Orally Active Pyrrolidone Derivatives as Novel Inhibitors of p53-MDM2 Protein-Protein Interaction

作者：Zhuang Chunlin; Miao Zhenyuan; Zhu Lingjian; Dong Guoqiang; Guo Zizhao; Wang Shengzheng; Zhang Yongqiang; Wu Yuelin; Yao Jianzhong; Sheng Chunquan; Zhang Wannian^*

来源：Journal of Medicinal Chemistry, 2012, 55(22): 9630-9642.

DOI：10.1021/jm300969t

The p53-MDM2 interaction has been proved to,, be a valuable target, to develop effective antitumor agents. Novel p53-MDM2 inhibitors bearing pyrrolidone scaffolds were successfully identified by structure-based design. The nanomolar inhibitor 5 possessed good p53-MDM2 inhibitory activity (K-i = 780 nM) due to its hydrophobic and hydrogen bonding interactions with MDM2. Further hit optimization led to. the discovery of a number of highly potent pyrrolidone derivative%26apos;s with improved p537-MDM2 inhibitory activity and in vitro antiproliferative potency. Compounds 41 (K-i = 260.0 nM) and 60a (K-i = 150.0 nM) showed good and selective activity against tumor cells with deleted p53. In addition, these two Compounds also :effectively inhibited the tumor growth in the A549 xenograft model: Interestingly, compound 41 was proved to be a potent MDM2/MDMX dual inhibitor. The novel pyrrolidone p53-MDM2 inhibitors represent promising lead structures for the development Of novel antitumor agents.

• 出版日期2012-11-22
• 单位中国人民解放军第二军医大学