1-(4-(2-nitrophenyl)piperazin-1-yl)-2-(3-(trifluoromethyl)phenoxy)ethanone

• 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-(4-(2-nitrophenyl)piperazin-1-yl)-2-(3-(trifluoromethyl)phenoxy)ethanone
• 英文别名: 1-[4-(2-Nitrophenyl)piperazin-1-yl]-2-[3-(trifluoromethyl)phenoxy]ethanone
• 化学式: C₁₉H₁₈F₃N₃O₄
• 分子量: 409.365
• InChiKey: VRTPWKAVIUYGID-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  78.6
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  1-(2-硝基苯基)哌嗪 、 [3-(三氟甲基)苯氧基]乙酸 在 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 0.08h， 以28%的产率得到1-(4-(2-nitrophenyl)piperazin-1-yl)-2-(3-(trifluoromethyl)phenoxy)ethanone
  参考文献：
  名称：

  Discovery and synthetic optimization of a novel scaffold for hydrophobic tunnel-targeted autotaxin inhibition

  摘要：

  Autotaxin (ATX) is a ubiquitous ectoenzyme that hydrolyzes lysophosphatidylcholine (LPC) to form the bioactive lipid mediator lysophosphatidic acid (LPA). LPA activates specific G-protein coupled receptors to elicit downstream effects leading to cellular motility, survival, and invasion. Through these pathways, upregulation of ATX is linked to diseases such as cancer and cardiovascular disease. Recent crystal structures confirm that the catalytic domain of ATX contains multiple binding regions including a polar active site, hydrophobic tunnel, and a hydrophobic pocket. This finding is consistent with the promiscuous nature of ATX hydrolysis of multiple and diverse substrates and prior investigations of inhibitor impacts on ATX enzyme kinetics. The current study used virtual screening methods to guide experimental identification and characterization of inhibitors targeting the hydrophobic region of ATX. An initially discovered inhibitor, GRI392104 (IC50 4 mu M) was used as a lead for synthetic optimization. In total twelve newly synthesized inhibitors of ATX were more potent than GRI392104 and were selective for ATX as they had no effect on other LPC-specific NPP family members or on LPA(1-5) GPCR. (C) 2016 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2016.08.004

文献信息

• Discovery and synthetic optimization of a novel scaffold for hydrophobic tunnel-targeted autotaxin inhibition
  作者：Lauren E. Ragle、Dilip J. Palanisamy、Margaux J. Joe、Rachel S. Stein、Derek D. Norman、Gabor Tigyi、Daniel L. Baker、Abby L. Parrill

  DOI：10.1016/j.bmc.2016.08.004

  日期：2016.10

  Autotaxin (ATX) is a ubiquitous ectoenzyme that hydrolyzes lysophosphatidylcholine (LPC) to form the bioactive lipid mediator lysophosphatidic acid (LPA). LPA activates specific G-protein coupled receptors to elicit downstream effects leading to cellular motility, survival, and invasion. Through these pathways, upregulation of ATX is linked to diseases such as cancer and cardiovascular disease. Recent crystal structures confirm that the catalytic domain of ATX contains multiple binding regions including a polar active site, hydrophobic tunnel, and a hydrophobic pocket. This finding is consistent with the promiscuous nature of ATX hydrolysis of multiple and diverse substrates and prior investigations of inhibitor impacts on ATX enzyme kinetics. The current study used virtual screening methods to guide experimental identification and characterization of inhibitors targeting the hydrophobic region of ATX. An initially discovered inhibitor, GRI392104 (IC50 4 mu M) was used as a lead for synthetic optimization. In total twelve newly synthesized inhibitors of ATX were more potent than GRI392104 and were selective for ATX as they had no effect on other LPC-specific NPP family members or on LPA(1-5) GPCR. (C) 2016 Elsevier Ltd. All rights reserved.