tert-butyl 4-(4-(4-fluorophenyl)-5-(2-(methylthio)-pyrimidin-4-yl)-1H-imidazol-1-yl)piperidine-1-carboxylate | 180869-52-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: tert-butyl 4-(4-(4-fluorophenyl)-5-(2-(methylthio)-pyrimidin-4-yl)-1H-imidazol-1-yl)piperidine-1-carboxylate
• 英文别名: 5-(2-methylthio-4-pyrimidinyl)-4-(4-fluorophenyl)-1-[(1-t-butoxycarbonyl)-4-piperidinyl]imidazole；Tert-butyl 4-[4-(4-fluorophenyl)-5-(2-methylsulfanylpyrimidin-4-yl)imidazol-1-yl]piperidine-1-carboxylate
• CAS: 180869-52-7
• 化学式: C₂₄H₂₈FN₅O₂S
• 分子量: 469.583
• InChiKey: CPZJFVCDBMTVIE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  33
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  98.4
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  tert-butyl 4-(4-(4-fluorophenyl)-5-(2-(methylthio)-pyrimidin-4-yl)-1H-imidazol-1-yl)piperidine-1-carboxylate 在 oxone 、 sodium hydride 作用下， 以 四氢呋喃 、 水 、 mineral oil 为溶剂， 反应 24.67h， 生成 tert-butyl 4-(5-(2-(3,5-dimethylphenoxy)pyrimidin-4-yl)-4-(4-fluorophenyl)-1H-imidazol-1-yl)piperidine-1-carboxylate
  参考文献：
  名称：

  Molecular Basis for the N-Terminal Bromodomain-and-Extra-Terminal-Family Selectivity of a Dual Kinase–Bromodomain Inhibitor

  摘要：

  As regulators of transcription, epigenetic proteins that interpret post-translational modifications to N-terminal histone tails are essential for maintaining cellular homeostasis. When dysregulated, "reader" proteins become drivers of disease. In the case of bromodomains, which recognize N-epsilon-acetylated lysine, selective inhibition of individual bromodomain-and-extra-terminal (BET)family bromodomains has proven challenging. We describe the >55-fold N-terminal-BET bromodomain selectivity of 1,4,5-trisubstituted-imidazole dual kinase-bromodomain inhibitors. Selectivity for the BRD4 N-terminal bromodomain (BRD4(1)) over its second bromodomain (BRD4(2)) arises from the displacement of ordered waters and the conformational flexibility of lysine-141 in BRD4(1). Cellular efficacy was demonstrated via reduction of c-Myc expression, inhibition of NF-kappa B signaling, and suppression of IL-8 production through potential synergistic inhibition of BRD4(1) and p38a. These dual inhibitors provide a new scaffold for domain-selective inhibition of BRD4, the aberrant function of which plays a key role in cancer and inflammatory signaling.

  DOI：

  10.1021/acs.jmedchem.8b01248
• 作为产物：
  描述：

  4-(二甲氧甲基)-2-甲硫基嘧啶 在 盐酸 、 magnesium sulfate 、 potassium carbonate 作用下， 以 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 88.0h， 生成 tert-butyl 4-(4-(4-fluorophenyl)-5-(2-(methylthio)-pyrimidin-4-yl)-1H-imidazol-1-yl)piperidine-1-carboxylate
  参考文献：
  名称：

  Molecular Basis for the N-Terminal Bromodomain-and-Extra-Terminal-Family Selectivity of a Dual Kinase–Bromodomain Inhibitor

  摘要：

  As regulators of transcription, epigenetic proteins that interpret post-translational modifications to N-terminal histone tails are essential for maintaining cellular homeostasis. When dysregulated, "reader" proteins become drivers of disease. In the case of bromodomains, which recognize N-epsilon-acetylated lysine, selective inhibition of individual bromodomain-and-extra-terminal (BET)family bromodomains has proven challenging. We describe the >55-fold N-terminal-BET bromodomain selectivity of 1,4,5-trisubstituted-imidazole dual kinase-bromodomain inhibitors. Selectivity for the BRD4 N-terminal bromodomain (BRD4(1)) over its second bromodomain (BRD4(2)) arises from the displacement of ordered waters and the conformational flexibility of lysine-141 in BRD4(1). Cellular efficacy was demonstrated via reduction of c-Myc expression, inhibition of NF-kappa B signaling, and suppression of IL-8 production through potential synergistic inhibition of BRD4(1) and p38a. These dual inhibitors provide a new scaffold for domain-selective inhibition of BRD4, the aberrant function of which plays a key role in cancer and inflammatory signaling.

  DOI：

  10.1021/acs.jmedchem.8b01248

文献信息

• Substituted imidazole compounds
  申请人：SmithKline Beecham Corporation

  公开号：US05716955A1

  公开（公告）日：1998-02-10

  Novel 1,4,5-substituted imidazole compounds and compositions for use in therapy as cytokine inhibitors.

  新型1,4,5-取代咪唑化合物及其在治疗中作为细胞因子抑制剂使用的组合物。
• Imidazole compounds and compositions
  申请人：SmithKline Beecham Corporation

  公开号：US05739143A1

  公开（公告）日：1998-04-14

  Novel 1,4,5-substituted imidazole compounds and compositions for use in therapy as cytokine inhibitors.

  新型1,4,5-取代咪唑化合物及其在治疗中作为细胞因子抑制剂使用的组合物。
• Imidazole compounds, compositions and use
  申请人：SmithKline Beecham Corporation

  公开号：US05658903A1

  公开（公告）日：1997-08-19

  Novel 1,4,5-substituted imidazole compounds and compositions for use in therapy as cytokine inhibitors.

  1,4,5-取代咪唑化合物及其在治疗中作为细胞因子抑制剂使用的组合物。
• Process for making pyridyl and pyrimidine substituted imidazole compounds
  申请人：SmithKline Beecham Corporation

  公开号：US06218537B1

  公开（公告）日：2001-04-17

  1,4,5,-substituted imidazole compounds and compositions for use in therapy as cytokine inhibitors.

  1,4,5-取代咪唑化合物和组合物，用于作为细胞因子抑制剂的治疗。
• Process for the preparation of Tosylbenzylformamides
  申请人：SMITHKLINE BEECHAM CORPORATION

  公开号：EP1264827A1

  公开（公告）日：2002-12-11

  A process for preparing tosylbenzyl formamides.

  一种制备对甲苯基苄基甲酰胺的工艺。