Departments of Therapeutic Discovery, ‡Pharmaceutics, and §Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California, 94080, United States.
J Med Chem. 2014 Feb 27;57(4):1454-72. doi: 10.1021/jm401753e. Epub 2014 Feb 5.
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 KD = 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).
我们最近报道了 AM-8553（1）的发现，这是一种强效且选择性的哌啶酮抑制剂，可抑制 MDM2-p53 相互作用。对该系列中 N- 烷基取代基的持续研究调查，特别关注 MDM2 表面浅裂缝中以前未充分利用的相互作用，导致发现了一个一碳连接的砜，从而使生化和细胞效力得到了实质性提高。进一步的研究产生了 AMG 232（2），目前正在进行人类临床试验，用于癌症治疗。化合物 2 是一种极其有效的 MDM2 抑制剂（SPR KD = 0.045 nM，SJSA-1 EdU IC50 = 9.1 nM），具有出色的药代动力学特性和体内抗肿瘤活性，在 SJSA-1 骨肉瘤异种移植模型中（ED50 = 9.1 mg/kg）。
