2-(4-benzoylphenoxy)-N-(pyridin-3-yl)acetamide | 791127-70-3

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 2-(4-benzoylphenoxy)-N-(pyridin-3-yl)acetamide
• 英文别名: 2-(4-benzoylphenoxy)-N-pyridin-3-ylacetamide
• CAS: 791127-70-3
• 化学式: C₂₀H₁₆N₂O₃
• 分子量: 332.359
• InChiKey: FNMUQXAXWHYNQS-UHFFFAOYSA-N

物化性质

• 沸点：
  595.8±40.0 °C(Predicted)
• 密度：
  1.267±0.06 g/cm3(Predicted)
• 溶解度：
  >49.9 [ug/mL]

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  25
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.05
• 拓扑面积：
  68.3
• 氢给体数：
  1
• 氢受体数：
  4

制备方法与用途

一种有效的选择性hERG钾通道(Kv11.1)激活剂，其EC50值为3.13 μM；对KCNQ1和KCNE1没有增强作用，并且不会显著影响其他心脏通道，包括Cav1.2、Kir2.1、Nav1.5和Kv4.3；在hERG稳态电流的10 μM CHO细胞中显着增强了电流和尾电流，在iPSC衍生的心肌细胞中也增强了天然钾电流。该化合物还缩短了LQT1心肌细胞的APD90，并且其EC50值为5.71 μM，从而能够使患者来源的心肌细胞疾病表型恢复正常，用于治疗LQT1相关疾病。

反应信息

• 作为产物：
  描述：

  (3-bromo-4-methoxyphenyl)-phenylmethanone 在 aluminum (III) chloride 、 水 、 potassium carbonate 、 三乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 、 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 生成 2-(4-benzoylphenoxy)-N-(pyridin-3-yl)acetamide
  参考文献：
  名称：

  Synthesis and biological evaluation of negative allosteric modulators of the Kv11.1(hERG) channel

  摘要：

  We synthesized and evaluated a series of compounds for their allosteric modulation at the K(v)11.1 (hERG) channel. Most compounds were negative allosteric modulators of [H-3]dofetilide binding to the channel, in particular 7f, 7h-j and 7p. Compounds 7f and 7p were the most potent negative allosteric modulators amongst all ligands, significantly increasing the dissociation rate of dofetilide in the radioligand kinetic binding assay, while remarkably reducing the affinities of dofetilide and astemizole in a competitive displacement assay. Additionally, both 7f and 7p displayed peculiar displacement characteristics with Hill coefficients significantly distinct from unity as shown by e.g., dofetilide, further indicative of their allosteric effects on dofetilide binding. Our findings in this investigation yielded several promising negative allosteric modulators for future functional and clinical research with respect to their antiarrhythmic propensities, either alone or in combination with known K(v)11.1 blockers. (C) 2015 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2015.10.032

文献信息

• Synthesis and biological evaluation of negative allosteric modulators of the Kv11.1(hERG) channel
  作者：Zhiyi Yu、Jacobus P.D. van Veldhoven、Ingrid M.E. 't Hart、Adrian H. Kopf、Laura H. Heitman、Adriaan P. IJzerman

  DOI：10.1016/j.ejmech.2015.10.032

  日期：2015.12

  We synthesized and evaluated a series of compounds for their allosteric modulation at the K(v)11.1 (hERG) channel. Most compounds were negative allosteric modulators of [H-3]dofetilide binding to the channel, in particular 7f, 7h-j and 7p. Compounds 7f and 7p were the most potent negative allosteric modulators amongst all ligands, significantly increasing the dissociation rate of dofetilide in the radioligand kinetic binding assay, while remarkably reducing the affinities of dofetilide and astemizole in a competitive displacement assay. Additionally, both 7f and 7p displayed peculiar displacement characteristics with Hill coefficients significantly distinct from unity as shown by e.g., dofetilide, further indicative of their allosteric effects on dofetilide binding. Our findings in this investigation yielded several promising negative allosteric modulators for future functional and clinical research with respect to their antiarrhythmic propensities, either alone or in combination with known K(v)11.1 blockers. (C) 2015 Elsevier Masson SAS. All rights reserved.