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 Apr 10;57(7):2963-88. doi: 10.1021/jm401911v. Epub 2014 Mar 27.
We previously reported the discovery of potent and selective morpholinone and piperidinone inhibitors of the MDM2-p53 interaction. These inhibitors have in common a carboxylic acid moiety that engages in an electrostatic interaction with MDM2-His96. Our continued search for potent and diverse inhibitors led to the discovery of novel replacements for these acids uncovering new interactions with the MDM2 protein. In particular, using pyridine or thiazole as isosteres of the carboxylic acid moiety resulted in very potent analogues. From these, AM-6761 (4) emerged as a potent inhibitor with remarkable biochemical (HTRF IC50 = 0.1 nM) and cellular potency (SJSA-1 EdU IC50 = 16 nM), as well as favorable pharmacokinetic properties. Compound 4 also shows excellent antitumor activity in the SJSA-1 osteosarcoma xenograft model with an ED50 of 11 mg/kg. Optimization efforts toward the discovery of these inhibitors as well as the new interactions observed with the MDM2 protein are described herein.
我们之前报道了发现强效且选择性的吗啉酮和哌啶酮类 MDM2-p53 相互作用抑制剂。这些抑制剂的共同点是含有羧酸部分，与 MDM2-His96 发生静电相互作用。我们继续寻找强效且多样的抑制剂，发现了这些酸的新型替代品，揭示了与 MDM2 蛋白的新相互作用。特别是，使用吡啶或噻唑作为羧酸部分的等排体，得到了非常强效的类似物。其中，AM-6761（4）作为一种强效抑制剂脱颖而出，具有显著的生化（HTRF IC50=0.1 nM）和细胞效力（SJSA-1 EdU IC50=16 nM），以及良好的药代动力学性质。化合物 4 在 SJSA-1 骨肉瘤异种移植模型中也表现出优异的抗肿瘤活性，ED50 为 11 mg/kg。本文描述了这些抑制剂的发现以及与 MDM2 蛋白观察到的新相互作用的优化工作。
