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首页> 外文期刊>Journal of Medicinal Chemistry >Novel Inhibitors of the MDM2-p53 Interaction Featuring Hydrogen Bond Acceptors as Carboxylic Acid Isosteres
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Novel Inhibitors of the MDM2-p53 Interaction Featuring Hydrogen Bond Acceptors as Carboxylic Acid Isosteres

机译：MDM2-p53相互作用的新型抑制剂，具有氢键受体作为羧酸的等排异构体

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摘要

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 IC_(50) = 0.1 nM) and cellular potency (SJSA-1 EdU IC_(50) = 16 nM), as well as favorable pharmacokinetic properties. Compound 4 also shows excellent antitumor activity in the SJSA-1 osteosarcoma xenograft model with an ED_(50) 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.
机译：我们之前曾报道过发现MDM2-p53相互作用的有效和选择性吗啉酮和哌啶酮抑制剂的发现。这些抑制剂共同具有与MDM2-His96发生静电相互作用的羧酸部分。我们一直在寻找有效和多样的抑制剂，从而发现了这些酸的新型替代物，从而发现了与MDM2蛋白的新相互作用。特别地，使用吡啶或噻唑作为羧酸部分的等排体产生非常有效的类似物。从这些化合物中，AM-6761（4）成为具有显着生化作用（HTRF IC_（50）= 0.1 nM）和细胞效价（SJSA-1 EdU IC_（50）= 16 nM）的有效抑制剂，并且具有良好的药代动力学特性。化合物4在SJSA-1骨肉瘤异种移植模型中也显示出优异的抗肿瘤活性，ED_（50）为11 mg / kg。本文描述了对发现这些抑制剂以及与MDM2蛋白观察到的新相互作用的优化努力。

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