[2-(4-tert-butyl-2-ethoxyphenyl)-4,5-dihydroimidazol-1-yl]-[4-(3-methanesulfonylpropyl)piperazin-1-yl]methanone | 1440433-55-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: [2-(4-tert-butyl-2-ethoxyphenyl)-4,5-dihydroimidazol-1-yl]-[4-(3-methanesulfonylpropyl)piperazin-1-yl]methanone
• 英文别名: [2-(4-Tert-butyl-2-ethoxyphenyl)-4,5-dihydroimidazol-1-yl]-[4-(3-methylsulfonylpropyl)piperazin-1-yl]methanone；[2-(4-tert-butyl-2-ethoxyphenyl)-4,5-dihydroimidazol-1-yl]-[4-(3-methylsulfonylpropyl)piperazin-1-yl]methanone
• CAS: 1440433-55-5
• 化学式: C₂₄H₃₈N₄O₄S
• 分子量: 478.656
• InChiKey: ZYZAKUFTLHXEHK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  33
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  90.9
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  4-叔丁基-2-乙氧基苯甲酸甲酯 在 光气 、 三甲基铝 、 三乙胺 作用下， 以 二氯甲烷 、 甲苯 为溶剂， 反应 1.5h， 生成 [2-(4-tert-butyl-2-ethoxyphenyl)-4,5-dihydroimidazol-1-yl]-[4-(3-methanesulfonylpropyl)piperazin-1-yl]methanone
  参考文献：
  名称：

  Deconstruction of a Nutlin: Dissecting the Binding Determinants of a Potent Protein–Protein Interaction Inhibitor

  摘要：

  Protein-protein interaction (PPI) systems represent a rich potential source of targets for drug discovery, but historically have proven to be difficult, particularly in the lead. identification stage. Application of the fragment-based approach may help toward success with this target class. To provide an example toward understanding the potential issues associated with such an application, we have deconstructed one of the best established protein-protein inhibitors, the Nutlin series that inhibits the interaction between MDM2 and p53, into fragments, and surveyed the resulting binding properties using heteronuclear single quantum coherence nuclear magnetic resonance (HSQC NMR), surface plasmon resonance (SPR), and X-ray crystallography. We report the relative contributions toward binding affinity for each key substituents of the Nutlin molecule and show that this series could hypothetically have been discovered via fragment approach. We find that the smallest fragment of Nutlin that retains binding accesses two subpockets of MDM2 and has a molecular weight at the high end of the range that normally defines fragments.

  DOI：

  10.1021/ml400062c

文献信息

• Deconstruction of a Nutlin: Dissecting the Binding Determinants of a Potent Protein–Protein Interaction Inhibitor
  作者：David C. Fry、Charles Wartchow、Bradford Graves、Cheryl Janson、Christine Lukacs、Ursula Kammlott、Charles Belunis、Stefan Palme、Christian Klein、Binh Vu

  DOI：10.1021/ml400062c

  日期：2013.7.11

  Protein-protein interaction (PPI) systems represent a rich potential source of targets for drug discovery, but historically have proven to be difficult, particularly in the lead. identification stage. Application of the fragment-based approach may help toward success with this target class. To provide an example toward understanding the potential issues associated with such an application, we have deconstructed one of the best established protein-protein inhibitors, the Nutlin series that inhibits the interaction between MDM2 and p53, into fragments, and surveyed the resulting binding properties using heteronuclear single quantum coherence nuclear magnetic resonance (HSQC NMR), surface plasmon resonance (SPR), and X-ray crystallography. We report the relative contributions toward binding affinity for each key substituents of the Nutlin molecule and show that this series could hypothetically have been discovered via fragment approach. We find that the smallest fragment of Nutlin that retains binding accesses two subpockets of MDM2 and has a molecular weight at the high end of the range that normally defines fragments.