(2-(4-(tert-butyl)-2-ethoxyphenyl)-4,5-bis(4-chlorophenyl)-4,5-dihydro-1H-imidazol-1-yl)(piperazin-1-yl)methanone

• 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: (2-(4-(tert-butyl)-2-ethoxyphenyl)-4,5-bis(4-chlorophenyl)-4,5-dihydro-1H-imidazol-1-yl)(piperazin-1-yl)methanone
• 英文别名: [(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis(4-chlorophenyl)-4,5-dihydroimidazol-1-yl]-piperazin-1-ylmethanone
• 化学式: C₃₂H₃₆Cl₂N₄O₂
• 分子量: 579.569
• InChiKey: FLVZHJXGYBGXDA-URLMMPGGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.7
• 重原子数：
  40
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  57.2
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (2-(4-(tert-butyl)-2-ethoxyphenyl)-4,5-bis(4-chlorophenyl)-4,5-dihydro-1H-imidazol-1-yl)(piperazin-1-yl)methanone 在 bis-triphenylphosphine-palladium(II) chloride 、 copper(l) iodide 、 三乙胺 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 三氟乙酸 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 8.0h， 生成 N-(2-(4-(2-(4-(tert-butyl)-2-ethoxyphenyl)-4,5-bis(4-chlorophenyl)-4,5-dihydro-1H-imidazole-1-carbonyl)piperazin-1-yl)-2-oxoethyl)-7-(2-(2-methylene-6-oxopiperidin-3-yl)-1-oxoisoindolin-4-yl)hept-6-ynamide
  参考文献：
  名称：

  Development of selective small molecule MDM2 degraders based on nutlin

  摘要：

  Tumor suppressor protein p53 is important to the regulation of many cellular processes and the prevention of cancer development. In some cancer cells, the function of p53 is inhibited by murine double minute 2 protein (MDM2). To restore the function of p53, the inhibition or depletion of MDM2 has become a potential therapeutic treatment. We have successfully developed a series of small molecule MDM2 degraders that can promote the proteolysis of MDM2 oncoprotein, thus reactivating tumor suppressor p53. The superior degrader features a nutlin-based MDM2 ligand and a lenalidomide-based cereblon E3 ubiquitin ligase ligand with a short linker between the two ligands. At low nanomolar concentrations in RS4; 11 leukemia cells, this degrader promotes efficient degradation of MDM2. It also inhibits the proliferation of leukemia cells with an IC50 value of 3.2 nM and induces apoptosis effectively. All of these data indicate that MDM2 degraders are promising therapeutics for the treatment of cancers, such as leukemia. (C) 2019 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2019.05.046
• 作为产物：
  描述：

  2-乙氧基-4-叔丁基苯甲酸 在 4-二甲氨基吡啶 、 三氟甲磺酸酐 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三氟乙酸 、 三苯基氧化膦 作用下， 以 二氯甲烷 为溶剂， 反应 23.5h， 生成 (2-(4-(tert-butyl)-2-ethoxyphenyl)-4,5-bis(4-chlorophenyl)-4,5-dihydro-1H-imidazol-1-yl)(piperazin-1-yl)methanone
  参考文献：
  名称：

  [EN] BIFUNCTIONAL NUTLIN-LENALIDOMIDE DERIVATIVES ((4,5-DIHYDRO-1H-IMIDAZOLE-1-CARBONYL)PIPERAZIN-1-YL-[LINKER]-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE DERIVATIVES) AS MDM2 DEGRADERS AND MDM2-P53 INHIBITORS FOR USE IN CANCER THERAPY
  [FR] DÉRIVÉS BIFONCTIONNELS DE NUTLINE-LÉNALIDOMIDE (DÉRIVÉS DE LA (4,5-DIHYDRO-1H-IMIDAZOLE-1-CARBONYL)PIPÉRAZIN-1-YL-[LIEUR]-1-OXOISOINDOLIN-2-YL)PIPÉRIDINE-2,6-DIONE) UTILISÉS COMME AGENTS DE DÉGRADATION DE MDM2 ET COMME INHIBITEURS DE MDM2-P53 DESTINÉS À ÊTRE UTILISÉS DANS LE TRAITEMENT DU CANCER

  摘要：

  双功能nutlin-lenalidomide衍生物((4,5-二氢-lH-咪唑-1-羰基)哌嗪-1-基-[连接剂]-1-氧代异吲哚-2-基)哌啶-2,6-二酮衍生物)的化学式(I)，作为MDM2 (murine double minute 2)降解剂和MDM2-p53相互作用抑制剂，用于抑制肿瘤细胞生长和癌症治疗。

  公开号：

  WO2020232115A1

文献信息

• [EN] BIFUNCTIONAL NUTLIN-LENALIDOMIDE DERIVATIVES ((4,5-DIHYDRO-1H-IMIDAZOLE-1-CARBONYL)PIPERAZIN-1-YL-[LINKER]-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE DERIVATIVES) AS MDM2 DEGRADERS AND MDM2-P53 INHIBITORS FOR USE IN CANCER THERAPY<br/>[FR] DÉRIVÉS BIFONCTIONNELS DE NUTLINE-LÉNALIDOMIDE (DÉRIVÉS DE LA (4,5-DIHYDRO-1H-IMIDAZOLE-1-CARBONYL)PIPÉRAZIN-1-YL-[LIEUR]-1-OXOISOINDOLIN-2-YL)PIPÉRIDINE-2,6-DIONE) UTILISÉS COMME AGENTS DE DÉGRADATION DE MDM2 ET COMME INHIBITEURS DE MDM2-P53 DESTINÉS À ÊTRE UTILISÉS DANS LE TRAITEMENT DU CANCER
  申请人：WISCONSIN ALUMNI RES FOUND

  公开号：WO2020232115A1

  公开（公告）日：2020-11-19

  Bifunctional nutlin-lenalidomide derivatives ((4,5-dihydro-lH- imidazole-l-carbonyl) piperazin-l-yl-[linker]-l-oxoisoindolin-2-yl) piperidine-2, 6-dione derivatives) of the formula (I),as MDM2 (murine double minute 2) degraders and MDM2-p53 interaction inhibitors for use in inhibiting neoplastic cell growth and cancer therapy

  双功能nutlin-lenalidomide衍生物((4,5-二氢-lH-咪唑-1-羰基)哌嗪-1-基-[连接剂]-1-氧代异吲哚-2-基)哌啶-2,6-二酮衍生物)的化学式(I)，作为MDM2 (murine double minute 2)降解剂和MDM2-p53相互作用抑制剂，用于抑制肿瘤细胞生长和癌症治疗。
• CHIRAL CIS-IMIDAZOLINES
  申请人：Fotouhi Nader

  公开号：US20090143364A1

  公开（公告）日：2009-06-04

  and the pharmaceutically acceptable salts and esters thereof, wherein X 1 , X 2 , X 3 , Y 1 , Y 2 and R are described herein inhibit the interaction of MDM2 protein with a p53-like peptide and hence have anti proliferative activity.

  本文中的药物可接受的盐和酯，其中X1、X2、X3、Y1、Y2和R的描述抑制MDM2蛋白与类p53肽的相互作用，因此具有抗增殖活性。
• NOVEL CIS-IMIDAZOLINES
  申请人：F.HOFFMANN-LA ROCHE AG

  公开号：EP1753727B1

  公开（公告）日：2008-11-19
• US7964724B2
  申请人：——

  公开号：US7964724B2

  公开（公告）日：2011-06-21
• Development of selective small molecule MDM2 degraders based on nutlin
  作者：Bo Wang、Suzhen Wu、Jin Liu、Ka Yang、Haibo Xie、Weiping Tang

  DOI：10.1016/j.ejmech.2019.05.046

  日期：2019.8

  Tumor suppressor protein p53 is important to the regulation of many cellular processes and the prevention of cancer development. In some cancer cells, the function of p53 is inhibited by murine double minute 2 protein (MDM2). To restore the function of p53, the inhibition or depletion of MDM2 has become a potential therapeutic treatment. We have successfully developed a series of small molecule MDM2 degraders that can promote the proteolysis of MDM2 oncoprotein, thus reactivating tumor suppressor p53. The superior degrader features a nutlin-based MDM2 ligand and a lenalidomide-based cereblon E3 ubiquitin ligase ligand with a short linker between the two ligands. At low nanomolar concentrations in RS4; 11 leukemia cells, this degrader promotes efficient degradation of MDM2. It also inhibits the proliferation of leukemia cells with an IC50 value of 3.2 nM and induces apoptosis effectively. All of these data indicate that MDM2 degraders are promising therapeutics for the treatment of cancers, such as leukemia. (C) 2019 Elsevier Masson SAS. All rights reserved.