[(4R,5S)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazol-1-yl][4-(3-methanesulfonylpropyl)piperazin-1-yl]methanone | 1313611-27-6

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 二苯乙烯类
• 英文名称: [(4R,5S)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazol-1-yl][4-(3-methanesulfonylpropyl)piperazin-1-yl]methanone
• 英文别名: RG7112；((4R,5S)-2-(4-(tert-Butyl)-2-ethoxyphenyl)-4,5-bis(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-1-yl)(4-(3-(methylsulfonyl)propyl)piperazin-1-yl)methanone；[(4R,5S)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis(4-chlorophenyl)-4,5-dimethylimidazol-1-yl]-[4-(3-methylsulfonylpropyl)piperazin-1-yl]methanone
• CAS: 1313611-27-6
• 化学式: C₃₈H₄₈Cl₂N₄O₄S
• 分子量: 727.796
• InChiKey: QBGKPEROWUKSBK-AMAPPZPBSA-N

物化性质

• 沸点：
  790.4±70.0 °C(Predicted)
• 密度：
  1.23±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  7.3
• 重原子数：
  49
• 可旋转键数：
  10
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.47
• 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：

  (4R,5s)-2-(4-(叔丁基)-2-乙氧基苯基)-4,5-双(4-氯苯基)-4,5-二甲基-4,5-二氢-1H-咪唑 在 三乙胺 作用下， 以 二氯甲烷 、 甲苯 为溶剂， 反应 7.0h， 生成 [(4R,5S)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazol-1-yl][4-(3-methanesulfonylpropyl)piperazin-1-yl]methanone
  参考文献：
  名称：

  Discovery of RG7112: A Small-Molecule MDM2 Inhibitor in Clinical Development

  摘要：

  The p53 tumor suppressor is a potent transcription factor that plays a key role in the regulation of cellular responses to stress. It is controlled by its negative regulator MDM2, which binds directly to p53 and inhibits its transcriptional activity. MDM2 also targets p53 for degradation by the proteasome. Many tumors produce high levels of MDM2, thereby impairing p53 function. Restoration of p53 activity by inhibiting the p53-MDM2 interaction may represent a novel approach to cancer treatment. RG7112 (2g) is the first clinical small-molecule MDM2 inhibitor designed to occupy the p53-binding pocket of MDM2. In cancer cells expressing wild-type p53, RG7112 stabilizes p53 and activates the p53 pathway, leading to cell cycle arrest, apoptosis, and inhibition or regression of human tumor xenografts.

  DOI：

  10.1021/ml4000657

文献信息

• Application of PAT Tools for the Safe and Reliable Production of a Dihydro-1<i>H</i>-imidazole
  作者：Ana C. Barrios Sosa、Ryan Conway、R. Thomas Williamson、James P. Suchy、William Edwards、Thomas Cleary

  DOI：10.1021/op2001172

  日期：2011.11.18

  The application of two Process Analytical Technology (PAT) tools was studied and implemented for the safe and reliable synthesis of an advanced intermediate (4S,5R-7) of a member of the dihydro-1H-imidazole (1) class of compounds. Real time data were generated using ReactIR to track the complete breakdown of phosgene precursors (2) to phosgene (3) and confirm the absence of these hazardous materials prior to batch transfer operations. In addition, the chiral resolution by crystallization of rac 7 was monitored by a Lasentec FBRM probe-based system. Implementation of the latter helped to track the crystallization process to minimize the risk of cocrystallization of undesired isomer 4R,5S-7.
• 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.
• ARYL-SUBSTITUTED IMIDAZOLES
  申请人：St. Jude Children's Research Hospital

  公开号：US20190345141A1

  公开（公告）日：2019-11-14

  The compounds of the invention are antagonists of MDM2 and MDMX, with excellent specificity for MDM2 and MDMX over other proteins, and with selective binding affinity to MDMX over MDM2. The compounds can therefore regulate p53 activity and treat a variety of cancers. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.
• US9266860B2
  申请人：——

  公开号：US9266860B2

  公开（公告）日：2016-02-23
• Discovery of RG7112: A Small-Molecule MDM2 Inhibitor in Clinical Development
  作者：Binh Vu、Peter Wovkulich、Giacomo Pizzolato、Allen Lovey、Qingjie Ding、Nan Jiang、Jin-Jun Liu、Chunlin Zhao、Kelli Glenn、Yang Wen、Christian Tovar、Kathryn Packman、Lyubomir Vassilev、Bradford Graves

  DOI：10.1021/ml4000657

  日期：2013.5.9

  The p53 tumor suppressor is a potent transcription factor that plays a key role in the regulation of cellular responses to stress. It is controlled by its negative regulator MDM2, which binds directly to p53 and inhibits its transcriptional activity. MDM2 also targets p53 for degradation by the proteasome. Many tumors produce high levels of MDM2, thereby impairing p53 function. Restoration of p53 activity by inhibiting the p53-MDM2 interaction may represent a novel approach to cancer treatment. RG7112 (2g) is the first clinical small-molecule MDM2 inhibitor designed to occupy the p53-binding pocket of MDM2. In cancer cells expressing wild-type p53, RG7112 stabilizes p53 and activates the p53 pathway, leading to cell cycle arrest, apoptosis, and inhibition or regression of human tumor xenografts.