1,1,1,3,3,3-hexafluoropropan-2-yl 3-(1-benzyl-1H-pyrazol-3-yl)azetidine-1-carboxylate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 氮杂环丁烷
• 英文名称: 1,1,1,3,3,3-hexafluoropropan-2-yl 3-(1-benzyl-1H-pyrazol-3-yl)azetidine-1-carboxylate
• 英文别名: 1,1,1,3,3,3-Hexafluoropropan-2-yl 3-(1-benzylpyrazol-3-yl)azetidine-1-carboxylate；1,1,1,3,3,3-hexafluoropropan-2-yl 3-(1-benzylpyrazol-3-yl)azetidine-1-carboxylate
• 化学式: C₁₇H₁₅F₆N₃O₂
• 分子量: 407.315
• InChiKey: AMNQIKVPQLYCPR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  28
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.41
• 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：

  tert-butyl 3-[(2E)-3-(dimethylamino)prop-2-enoyl]azetidine-1-carboxylate 在 caesium carbonate 、 一水合肼 、 三乙胺 、 三氟乙酸 、 potassium iodide 作用下， 以 乙醇 、 二氯甲烷 、 乙腈 为溶剂， 反应 52.5h， 生成 1,1,1,3,3,3-hexafluoropropan-2-yl 3-(1-benzyl-1H-pyrazol-3-yl)azetidine-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

• Radiosynthesis and evaluation of a novel monoacylglycerol lipase radiotracer: 1,1,1,3,3,3-hexafluoropropan-2-yl-3-(1-benzyl-1H-pyrazol-3-yl)azetidine-1-[11C]carboxylate
  作者：Wakana Mori、Akiko Hatori、Yiding Zhang、Yusuke Kurihara、Tomoteru Yamasaki、Lin Xie、Katsushi Kumata、Kuan Hu、Masayuki Fujinaga、Ming-Rong Zhang

  DOI：10.1016/j.bmc.2019.06.037

  日期：2019.8

  tomography (PET), we report a new carbon-11-labeled radiotracer, namely 1,1,1,3,3,3-hexafluoropropan-2-yl-3-(1-benzyl-1H-pyrazol-3-yl)azetidine-1-[11C]carboxylate ([11C]6). Compound 6 exhibited high in vitro binding affinity (IC50 = 0.41 nM) to MAGL in the brain with a suitable lipophilicity (cLogD = 3.29). [11C]6 was synthesized by reacting 1,1,1,3,3,3-hexafluoropropanol (7) with [11C]phosgene ([11C]COCl2)

  单酰基甘油脂肪酶（MAGL）是一种主要的丝氨酸水解酶，可将2-花生四烯酸甘油酯（2-AG）水解为大脑中的花生四烯酸（AA）和甘油。由于2-AG和AA是大脑中的内源性生物活性配体，因此抑制MAGL是神经退行性疾病的诱人治疗靶标。在这项研究中，为了通过正电子发射断层扫描（PET）可视化MAGL，我们报告了一种新的碳11标记的放射性示踪剂，即1,1,1,3,3,3-六氟丙烷-2-基-3-（1-苄基-1H-吡唑-3-基）氮杂环丁烷-1- [11C]羧酸酯（[11C] 6）。化合物6对脑中的MAGL表现出高的体外结合亲和力（IC50 = 0.41 nM），并具有适当的亲脂性（cLogD = 3.29）。通过使1,1,1,3,3,3-六氟丙醇（7）与[11C]光气（[11C] COCl2）反应合成[11C] 6，然后与3-（1-苄基-1H-吡唑-3-基）氮杂环丁烷盐酸盐（8）反应，基于[11C]，放射化学产率为15
• 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.