4-(fluoromethyl)-N-(2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl)-N-(pyridin-2-yl)bicyclo[2.2.2]octane-1-carboxamide | 1350821-88-3

• 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: 4-(fluoromethyl)-N-(2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl)-N-(pyridin-2-yl)bicyclo[2.2.2]octane-1-carboxamide
• 英文别名: 4-(fluoromethyl)-N-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-N-pyridin-2-ylbicyclo[2.2.2]octane-1-carboxamide
• CAS: 1350821-88-3
• 化学式: C₂₈H₃₇FN₄O₂
• 分子量: 480.626
• InChiKey: WAEVDDXBNJUJNE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  35
• 可旋转键数：
  8
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  48.9
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  4-(fluoromethyl)bicyclo[2.2.2]octane-1-carboxylic acid 在 氯化亚砜 、 三乙胺 作用下， 以 乙腈 为溶剂， 反应 1.0h， 生成 4-(fluoromethyl)-N-(2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl)-N-(pyridin-2-yl)bicyclo[2.2.2]octane-1-carboxamide
  参考文献：
  名称：

  Design, synthesis and in vitro evaluation of bridgehead fluoromethyl analogs of N-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-N-(pyridin-2-yl)cyclohexanecarboxamide (WAY-100635) for the 5-HT1A receptor

  摘要：

  Fluorinated analogs that are related to the 5-hydroxytryptamine (5-HT1A) antagonist, N-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-N-(pyridin-2-yl)cyclohexanecarboxamide (WAY-100635), have been synthesized and their binding affinity for the 5-HT1A receptor and other neurotransmitter receptors (adrenoceptors, sigma receptors, and dopamine receptors), and serotonin transporters was examined in vitro. These ligands were designed to provide a possible potential positron emission tomography (PET) ligand with high metabolic stability. To this end, the cyclohexyl moiety in WAY-100635 and in O-desmethyl WAY-100635 was replaced by a bridge-fused ring (BFR) such as adamantyl, cubyl, bicyclo[2.2.2] octyl and bicyclo[2.2.1]heptyl to reduce the metabolic rate of the amide bond hydrolysis, while a fluoromethyl group was introduced on the other bridgehead of the BFR to prevent defluorination by HE elimination. All synthesized analogs displayed high affinity in the (sub)nanomolar range for the 5-HT1A receptor, comparable to WAY-100635. In addition, 6b, 6c and 6d were reasonably selective to the 5-HT1A receptor over the above mentioned receptors. In human hepatocytes, 6b showed a suitable metabolic stability.In conclusion, the obtained data provides a promising starting point for the synthesis of the corresponding F-18-labeled PET analogs. (C) 2011 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2011.06.023

文献信息

• Design, synthesis and in vitro evaluation of bridgehead fluoromethyl analogs of N-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-N-(pyridin-2-yl)cyclohexanecarboxamide (WAY-100635) for the 5-HT1A receptor
  作者：Rana Al Hussainy、Joost Verbeek、Dion van der Born、Jan Booij、J(Koos) D.M. Herscheid

  DOI：10.1016/j.ejmech.2011.06.023

  日期：2011.12

  Fluorinated analogs that are related to the 5-hydroxytryptamine (5-HT1A) antagonist, N-2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-N-(pyridin-2-yl)cyclohexanecarboxamide (WAY-100635), have been synthesized and their binding affinity for the 5-HT1A receptor and other neurotransmitter receptors (adrenoceptors, sigma receptors, and dopamine receptors), and serotonin transporters was examined in vitro. These ligands were designed to provide a possible potential positron emission tomography (PET) ligand with high metabolic stability. To this end, the cyclohexyl moiety in WAY-100635 and in O-desmethyl WAY-100635 was replaced by a bridge-fused ring (BFR) such as adamantyl, cubyl, bicyclo[2.2.2] octyl and bicyclo[2.2.1]heptyl to reduce the metabolic rate of the amide bond hydrolysis, while a fluoromethyl group was introduced on the other bridgehead of the BFR to prevent defluorination by HE elimination. All synthesized analogs displayed high affinity in the (sub)nanomolar range for the 5-HT1A receptor, comparable to WAY-100635. In addition, 6b, 6c and 6d were reasonably selective to the 5-HT1A receptor over the above mentioned receptors. In human hepatocytes, 6b showed a suitable metabolic stability.In conclusion, the obtained data provides a promising starting point for the synthesis of the corresponding F-18-labeled PET analogs. (C) 2011 Elsevier Masson SAS. All rights reserved.