1-methyl-4-(4-(4-(3-(pyridin-4-ylmethoxy)pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)piperazine | 1922153-19-2

• 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: 1-methyl-4-(4-(4-(3-(pyridin-4-ylmethoxy)pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)piperazine
• 英文别名: Piperazine, 1-methyl-4-[4-[4-[3-(4-pyridinylmethoxy)-4-pyridinyl]-1H-pyrazol-1-yl]phenyl]-；1-methyl-4-[4-[4-[3-(pyridin-4-ylmethoxy)pyridin-4-yl]pyrazol-1-yl]phenyl]piperazine
• CAS: 1922153-19-2
• 化学式: C₂₅H₂₆N₆O
• 分子量: 426.521
• InChiKey: AGTQLXBDJPXYLW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  32
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  59.3
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  1-(4-溴苯基)-4-甲基哌嗪 在 2,2,6,6-四甲基哌啶 、 正丁基锂 、 sodium hydride 、 三氟乙酸 作用下， 以 四氢呋喃 、 正己烷 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 50.08h， 生成 1-methyl-4-(4-(4-(3-(pyridin-4-ylmethoxy)pyridin-4-yl)-1H-pyrazol-1-yl)phenyl)piperazine
  参考文献：
  名称：

  Toward the Validation of Maternal Embryonic Leucine Zipper Kinase: Discovery, Optimization of Highly Potent and Selective Inhibitors, and Preliminary Biology Insight

  摘要：

  MELK kinase has been implicated in playing an important role in tumorigenesis. Our previous studies suggested that MELK is involved in the regulation of cell cycle and its genetic depletion leads to growth inhibition in a subset of high MELK-expressing basal-like breast cancer cell lines. Herein we describe the discovery and optimization of novel MELK inhibitors 8a and 8b that recapitulate the cellular effects observed by short hairpin ribonucleic acid (shRNA)-mediated MELK knockdown in cellular models. We also discovered a novel fluorine-induced hydrophobic collapse that locked the ligand in its bioactive conformation and led to a 20-fold gain in potency. These novel pharmacological inhibitors achieved high exposure in vivo and were well tolerated, which may allow further in vivo evaluation.

  DOI：

  10.1021/acs.jmedchem.6b00052

文献信息

• Toward the Validation of Maternal Embryonic Leucine Zipper Kinase: Discovery, Optimization of Highly Potent and Selective Inhibitors, and Preliminary Biology Insight
  作者：B. Barry Touré、John Giraldes、Troy Smith、Elizabeth R. Sprague、Yaping Wang、Simon Mathieu、Zhuoliang Chen、Yuji Mishina、Yun Feng、Yan Yan-Neale、Subarna Shakya、Dongshu Chen、Matthew Meyer、David Puleo、J. Tres Brazell、Christopher Straub、David Sage、Kirk Wright、Yanqiu Yuan、Xin Chen、Jose Duca、Sean Kim、Li Tian、Eric Martin、Kristen Hurov、Wenlin Shao

  DOI：10.1021/acs.jmedchem.6b00052

  日期：2016.5.26

  MELK kinase has been implicated in playing an important role in tumorigenesis. Our previous studies suggested that MELK is involved in the regulation of cell cycle and its genetic depletion leads to growth inhibition in a subset of high MELK-expressing basal-like breast cancer cell lines. Herein we describe the discovery and optimization of novel MELK inhibitors 8a and 8b that recapitulate the cellular effects observed by short hairpin ribonucleic acid (shRNA)-mediated MELK knockdown in cellular models. We also discovered a novel fluorine-induced hydrophobic collapse that locked the ligand in its bioactive conformation and led to a 20-fold gain in potency. These novel pharmacological inhibitors achieved high exposure in vivo and were well tolerated, which may allow further in vivo evaluation.