benzaldehyde O-6,6-difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yloxime | 1428573-85-6

• 分子结构分类: 有机化合物 - 有机1,3-偶极化合物 - 烯丙基型1,3-偶极有机化合物
• 英文名称: benzaldehyde O-6,6-difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yloxime
• 英文别名: N-[6,6-difluoro-1-(2-methyl-4-nitropyrazol-3-yl)azepan-4-yl]oxy-1-phenylmethanimine
• CAS: 1428573-85-6
• 化学式: C₁₇H₁₉F₂N₅O₃
• 分子量: 379.366
• InChiKey: GGGVCXLHKTTWBX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  27
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  88.5
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  benzaldehyde O-6,6-difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yloxime 在 palladium on activated charcoal 、 氢气 、 N,N-二异丙基乙胺 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 生成 N-(5-(3,3-difluoro-5-hydroxyazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)benzamide
  参考文献：
  名称：

  Probing Mechanisms of CYP3A Time-Dependent Inhibition Using a Truncated Model System

  摘要：

  Time-dependent inhibition (TDI) of cytochrome P450 (CYP) enzymes may incur serious undesirable drug-drug interactions and in rare cases drug-induced idiosyncratic toxicity. The reactive metabolites are often generated through multiple sequential biotransformations and form adducts with CYP enzymes to inactivate their function. The complexity of these processes makes addressing TDI liability very challenging. Strategies to mitigate TDI are therefore highly valuable in discovering safe therapies to benefit patients. In this Letter, we disclose our simplified approach toward addressing CYP3A TDI liabilities, guided by metabolic mechanism hypotheses. By adding a methyl group onto the a carbon of a basic amine, TDI activities of both the truncated and full molecules (7a and 11) were completely eliminated. We propose that truncated molecules, albeit with caveats, may be used as surrogates for full molecules to investigate TDI.

  DOI：

  10.1021/acsmedchemlett.5b00191
• 作为产物：
  描述：

  苯甲醛肟 在 盐酸 、 potassium fluoride 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 [双(2-甲氧基乙基)胺]三氟化硫 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 二甲基亚砜 、 乙腈 为溶剂， 反应 98.0h， 生成 benzaldehyde O-6,6-difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yloxime
  参考文献：
  名称：

  Probing Mechanisms of CYP3A Time-Dependent Inhibition Using a Truncated Model System

  摘要：

  Time-dependent inhibition (TDI) of cytochrome P450 (CYP) enzymes may incur serious undesirable drug-drug interactions and in rare cases drug-induced idiosyncratic toxicity. The reactive metabolites are often generated through multiple sequential biotransformations and form adducts with CYP enzymes to inactivate their function. The complexity of these processes makes addressing TDI liability very challenging. Strategies to mitigate TDI are therefore highly valuable in discovering safe therapies to benefit patients. In this Letter, we disclose our simplified approach toward addressing CYP3A TDI liabilities, guided by metabolic mechanism hypotheses. By adding a methyl group onto the a carbon of a basic amine, TDI activities of both the truncated and full molecules (7a and 11) were completely eliminated. We propose that truncated molecules, albeit with caveats, may be used as surrogates for full molecules to investigate TDI.

  DOI：

  10.1021/acsmedchemlett.5b00191

文献信息

• Probing Mechanisms of CYP3A Time-Dependent Inhibition Using a Truncated Model System
  作者：Xiaojing Wang、Minghua Sun、Connie New、Spencer Nam、Wesley P. Blackaby、Alastair J. Hodges、David Nash、Mizio Matteucci、Joseph P. Lyssikatos、Peter W. Fan、Suzanne Tay、Jae H. Chang

  DOI：10.1021/acsmedchemlett.5b00191

  日期：2015.8.13

  Time-dependent inhibition (TDI) of cytochrome P450 (CYP) enzymes may incur serious undesirable drug-drug interactions and in rare cases drug-induced idiosyncratic toxicity. The reactive metabolites are often generated through multiple sequential biotransformations and form adducts with CYP enzymes to inactivate their function. The complexity of these processes makes addressing TDI liability very challenging. Strategies to mitigate TDI are therefore highly valuable in discovering safe therapies to benefit patients. In this Letter, we disclose our simplified approach toward addressing CYP3A TDI liabilities, guided by metabolic mechanism hypotheses. By adding a methyl group onto the a carbon of a basic amine, TDI activities of both the truncated and full molecules (7a and 11) were completely eliminated. We propose that truncated molecules, albeit with caveats, may be used as surrogates for full molecules to investigate TDI.