2-[(1-bromonaphthalen-2-yl)oxy]-N-(pyridin-3-yl)acetamide | 712325-30-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: 2-[(1-bromonaphthalen-2-yl)oxy]-N-(pyridin-3-yl)acetamide
• 英文别名: VU0405601；2-(1-bromonaphthalen-2-yl)oxy-N-pyridin-3-ylacetamide
• CAS: 712325-30-9
• 化学式: C₁₇H₁₃BrN₂O₂
• 分子量: 357.206
• InChiKey: WLLRAGBPCSOJNH-UHFFFAOYSA-N

物化性质

• 沸点：
  584.8±35.0 °C(Predicted)
• 密度：
  1.523±0.06 g/cm3(Predicted)
• 溶解度：
  在DMSO中的溶解度为20mg/mL，澄清

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  22
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  51.2
• 氢给体数：
  1
• 氢受体数：
  3

制备方法与用途

一种有效的Kv11.1(hERG)通道变构调节剂，可以保护心脏组织免受hERG相关药物诱导的心律失常。研究显示，将多非利特的IC(50)从38.7纳摩尔增加到76.3纳摩尔，主要是通过减少细胞外环境对hERG阻滞剂的作用来实现的。这降低了hERG通道对抑制剂的敏感性，从而增强了其稳定性。

反应信息

• 作为产物：
  描述：

  3-氨基吡啶 、 (1-溴-萘-2-氧基)-乙酸 在 三乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以74%的产率得到2-[(1-bromonaphthalen-2-yl)oxy]-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.