tert-butyl 4-(4-(4-fluorophenyl)-5-(2-(methylsulfonyl)pyrimidin-4-yl)-1H-imidazol-1-yl)piperidine-1-carboxylate

• 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-(methylsulfonyl)pyrimidin-4-yl)-1H-imidazol-1-yl)piperidine-1-carboxylate
• 英文别名: 5-(2-Methylsulfonyl-4-pyrimidinyl)-4-(4-fluorophenyl)-1-[(1-t-butoxycarbonyl)-4-piperidinyl]imidazole；Tert-butyl 4-[4-(4-fluorophenyl)-5-(2-methylsulfonylpyrimidin-4-yl)imidazol-1-yl]piperidine-1-carboxylate
• 化学式: C₂₄H₂₈FN₅O₄S
• 分子量: 501.582
• InChiKey: ZVNSMSACMRAFRG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  35
• 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：
  116
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  tert-butyl 4-(4-(4-fluorophenyl)-5-(2-(methylsulfonyl)pyrimidin-4-yl)-1H-imidazol-1-yl)piperidine-1-carboxylate 在 sodium hydride 作用下， 以 四氢呋喃 、 二氯甲烷 、 mineral oil 为溶剂， 反应 0.92h， 生成
  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 、 Oxone 、 potassium carbonate 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 生成 tert-butyl 4-(4-(4-fluorophenyl)-5-(2-(methylsulfonyl)pyrimidin-4-yl)-1H-imidazol-1-yl)piperidine-1-carboxylate
  参考文献：
  名称：

  Phenoxypyrimidine inhibitors of p38α kinase

  摘要：

  As a continuation of our work with 1,4,5 substituted imidazole inhibitors of p38 alpha, we report a series of 1-(4-piperidinyl)-4-(4-fluorophenyl)-5-(2-phenoxy-4-pyrimidinyl) imidazoles related to 7. The componds have IC50's for inhibition of p38 alpha ranging from 6.0 to 650 nM. Statistical analysis of the p38 alpha inhibitor potencies shows a correlation of IC50's with the electron donating strength of low molecular weight substituents. (C) 2001 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(01)00163-9

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。
• Phenoxypyrimidine inhibitors of p38α kinase
  作者：Jeffrey C. Boehm、Michael J. Bower、Timothy F. Gallagher、Shouki Kassis、Stephen R. Johnson、Jerry L. Adams

  DOI：10.1016/s0960-894x(01)00163-9

  日期：2001.5

  As a continuation of our work with 1,4,5 substituted imidazole inhibitors of p38 alpha, we report a series of 1-(4-piperidinyl)-4-(4-fluorophenyl)-5-(2-phenoxy-4-pyrimidinyl) imidazoles related to 7. The componds have IC50's for inhibition of p38 alpha ranging from 6.0 to 650 nM. Statistical analysis of the p38 alpha inhibitor potencies shows a correlation of IC50's with the electron donating strength of low molecular weight substituents. (C) 2001 Elsevier Science Ltd. All rights reserved.
• US6214844B1
  申请人：——

  公开号：US6214844B1

  公开（公告）日：2001-04-10
• Molecular Basis for the N-Terminal Bromodomain-and-Extra-Terminal-Family Selectivity of a Dual Kinase–Bromodomain Inhibitor
  作者：Anand Divakaran、Siva K. Talluri、Alex M. Ayoub、Neeraj K. Mishra、Huarui Cui、John C. Widen、Norbert Berndt、Jin-Yi Zhu、Angela S. Carlson、Joseph J. Topczewski、Ernst K. Schonbrunn、Daniel A. Harki、William C. K. Pomerantz

  DOI：10.1021/acs.jmedchem.8b01248

  日期：2018.10.25

  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.