1,1,1,3,3,3-hexafluoropropan-2-yl 4-(1-phenyl-1H-pyrazol-3-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: 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(1-phenyl-1H-pyrazol-3-yl)piperidine-1-carboxylate
• 英文别名: 1,1,1,3,3,3-Hexafluoropropan-2-yl 4-(1-phenylpyrazol-3-yl)piperidine-1-carboxylate；1,1,1,3,3,3-hexafluoropropan-2-yl 4-(1-phenylpyrazol-3-yl)piperidine-1-carboxylate
• 化学式: C₁₈H₁₇F₆N₃O₂
• 分子量: 421.342
• InChiKey: JEZZQVWVDVULKU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  47.4
• 氢给体数：
  0
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  4-乙酰基哌啶-1-甲酸叔丁酯 在 氧气 、 copper diacetate 、 一水合肼 、 三乙胺 、 三氟乙酸 作用下， 以 乙醇 、 二氯甲烷 、 乙腈 为溶剂， 反应 158.05h， 生成 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(1-phenyl-1H-pyrazol-3-yl)piperidine-1-carboxylate
  参考文献：
  名称：

  Azetidine and Piperidine Carbamates as Efficient, Covalent Inhibitors of Monoacylglycerol Lipase

  摘要：

  Monoacylglycerol lipase (MAGL) is the main enzyme responsible for degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG) in the CNS. MAGL catalyzes the conversion of 2-AG to arachidonic acid (AA), a precursor to the proinflammatory eicosannoids such as prostaglandins. Herein we describe highly efficient MAGL inhibitors, identified through a parallel medicinal chemistry approach that highlighted the improved efficiency of azetidine and piperidine-derived carbamates. The discovery and optimization of 3-substituted azetidine carbamate irreversible inhibitors of MAGL were aided by the generation of inhibitor-bound MAGL crystal structures. Compound 6, a highly efficient and selective MAGL inhibitor against recombinant enzyme and in a cellular context, was tested in vivo and shown to elevate central 2-AG levels at a 10 mg/kg dose.

  DOI：

  10.1021/acs.jmedchem.7b01531

文献信息

• Azetidine and Piperidine Carbamates as Efficient, Covalent Inhibitors of Monoacylglycerol Lipase
  作者：Christopher R. Butler、Elizabeth M. Beck、Anthony Harris、Zhen Huang、Laura A. McAllister、Christopher W. am Ende、Kimberly Fennell、Timothy L. Foley、Kari Fonseca、Steven J. Hawrylik、Douglas S. Johnson、John D. Knafels、Scot Mente、G. Stephen Noell、Jayvardhan Pandit、Tracy B. Phillips、Justin R. Piro、Bruce N. Rogers、Tarek A. Samad、Jane Wang、Shuangyi Wan、Michael A. Brodney

  DOI：10.1021/acs.jmedchem.7b01531

  日期：2017.12.14

  Monoacylglycerol lipase (MAGL) is the main enzyme responsible for degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG) in the CNS. MAGL catalyzes the conversion of 2-AG to arachidonic acid (AA), a precursor to the proinflammatory eicosannoids such as prostaglandins. Herein we describe highly efficient MAGL inhibitors, identified through a parallel medicinal chemistry approach that highlighted the improved efficiency of azetidine and piperidine-derived carbamates. The discovery and optimization of 3-substituted azetidine carbamate irreversible inhibitors of MAGL were aided by the generation of inhibitor-bound MAGL crystal structures. Compound 6, a highly efficient and selective MAGL inhibitor against recombinant enzyme and in a cellular context, was tested in vivo and shown to elevate central 2-AG levels at a 10 mg/kg dose.