1-(4-bromo-3,5-dimethylphenoxy)propan-2-one

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: 1-(4-bromo-3,5-dimethylphenoxy)propan-2-one
• 英文别名: 1-(4-Bromo-3,5-dimethylphenoxy)propan-2-one
• 化学式: C₁₁H₁₃BrO₂
• 分子量: 257.127
• InChiKey: MPGPAEJVWCSMCR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  14
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  26.3
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  1-(4-bromo-3,5-dimethylphenoxy)propan-2-one 在 sodium tetrahydroborate 作用下， 以 甲醇 为溶剂， 生成 1-(4-Bromo-3,5-dimethylphenoxy)propan-2-ol
  参考文献：
  名称：

  Pharmacological profiling of JME-173, a novel mexiletine derivative combining dual anti-inflammatory/anti-spasmodic functions and limited action in Na+ channels

  摘要：

  Existing evidence suggests that the local anaesthetic mexiletine can be beneficial for patients with asthma. However, caution is required since anaesthesia of the airways inhibits protective bronchodilator neuronal reflexes, limiting applications in conditions of hyperirritable airways. Here, we describe the synthesis of a new series of mexiletine analogues, which were screened for reduced activity in Na+ channels and improved smooth muscle relaxant effects, that were evaluated using the patch-clamp technique and an isolated tracheal organ bath, respectively. JME-173 (1-(4-bromo-3,5-dimethylphenoxy)propan-2-amine) was the most effective among the four mexiletine analogues investigated. JME-173 was then studied in vivo using a murine model of lung inflammation induced by cigarette smoke (CS) and in vitro using neutrophil chemotaxis and mast cell degranulation assays. Finally, the JME-173 pharmacokinetic profile was assessed using HPLC-MS/MS bioanalytical method. JME-173 directly inhibited IL-8 (CXCL8)- and FMLP-induced human neutrophil chemotaxis and allergen-induced mast cell degranulation. After oral administration 1 h before CS exposure, JME-173 (50 mg/kg) strongly reduced the increased number of macrophages and neutrophils recovered in the bronchoalveolar effluent without altering lymphocyte counts. Pharmacokinetic experiments of JME-173 (10 mg/kg, orally) showed values of maximum concentration (C-max), maximum time (T-max), area under the blood concentration-time curve (AUC(0-t)) and area under the blood concentration-time curve from 0-Inf (AUC(0-inf)) of 163.3 + 38.3 ng/mL, 1.2 +/- 0.3 h, 729.4 +/- 118.3 ng*h/ml and 868.9 + 117.1 ng*h/ml (means + S.E.M.), respectively. Collectively, these findings suggest that JME-173 has the potential to be an effective oral treatment for diseases associated with bronchoconstriction and inflammation.

  DOI：

  10.1016/j.ejphar.2020.173367
• 作为产物：
  描述：

  4-溴-3,5-二甲酚 、 一氯丙酮 在 potassium carbonate 、 potassium iodide 作用下， 以 丙酮 为溶剂， 以90%的产率得到1-(4-bromo-3,5-dimethylphenoxy)propan-2-one
  参考文献：
  名称：

  Pharmacological profiling of JME-173, a novel mexiletine derivative combining dual anti-inflammatory/anti-spasmodic functions and limited action in Na+ channels

  摘要：

  Existing evidence suggests that the local anaesthetic mexiletine can be beneficial for patients with asthma. However, caution is required since anaesthesia of the airways inhibits protective bronchodilator neuronal reflexes, limiting applications in conditions of hyperirritable airways. Here, we describe the synthesis of a new series of mexiletine analogues, which were screened for reduced activity in Na+ channels and improved smooth muscle relaxant effects, that were evaluated using the patch-clamp technique and an isolated tracheal organ bath, respectively. JME-173 (1-(4-bromo-3,5-dimethylphenoxy)propan-2-amine) was the most effective among the four mexiletine analogues investigated. JME-173 was then studied in vivo using a murine model of lung inflammation induced by cigarette smoke (CS) and in vitro using neutrophil chemotaxis and mast cell degranulation assays. Finally, the JME-173 pharmacokinetic profile was assessed using HPLC-MS/MS bioanalytical method. JME-173 directly inhibited IL-8 (CXCL8)- and FMLP-induced human neutrophil chemotaxis and allergen-induced mast cell degranulation. After oral administration 1 h before CS exposure, JME-173 (50 mg/kg) strongly reduced the increased number of macrophages and neutrophils recovered in the bronchoalveolar effluent without altering lymphocyte counts. Pharmacokinetic experiments of JME-173 (10 mg/kg, orally) showed values of maximum concentration (C-max), maximum time (T-max), area under the blood concentration-time curve (AUC(0-t)) and area under the blood concentration-time curve from 0-Inf (AUC(0-inf)) of 163.3 + 38.3 ng/mL, 1.2 +/- 0.3 h, 729.4 +/- 118.3 ng*h/ml and 868.9 + 117.1 ng*h/ml (means + S.E.M.), respectively. Collectively, these findings suggest that JME-173 has the potential to be an effective oral treatment for diseases associated with bronchoconstriction and inflammation.

  DOI：

  10.1016/j.ejphar.2020.173367

文献信息

• Pharmacological profiling of JME-173, a novel mexiletine derivative combining dual anti-inflammatory/anti-spasmodic functions and limited action in Na+ channels
  作者：Douglas Pereira Pinto、Diego de Sá Coutinho、Katharinne Ingrid Moraes de Carvalho、Maximiliano R. Ferrero、Letícia Vallim da Silva、Gabriel Parreiras Estolano Silveira、Diego Medeiros da Silva、João Felipe Garcia Araújo、Aline C.A. Silva、Heliana Martins Pereira、Laís Bastos da Fonseca、Robson Xavier Faria、Marcus Vinicius Nora de Souza、Emerson Teixeira da Silva、Osvaldo Andrade Santos-Filho、Jorge Carlos Santos da Costa、Fábio Coelho Amendoeira、Marco Aurélio Martins

  DOI：10.1016/j.ejphar.2020.173367

  日期：2020.10

  Existing evidence suggests that the local anaesthetic mexiletine can be beneficial for patients with asthma. However, caution is required since anaesthesia of the airways inhibits protective bronchodilator neuronal reflexes, limiting applications in conditions of hyperirritable airways. Here, we describe the synthesis of a new series of mexiletine analogues, which were screened for reduced activity in Na+ channels and improved smooth muscle relaxant effects, that were evaluated using the patch-clamp technique and an isolated tracheal organ bath, respectively. JME-173 (1-(4-bromo-3,5-dimethylphenoxy)propan-2-amine) was the most effective among the four mexiletine analogues investigated. JME-173 was then studied in vivo using a murine model of lung inflammation induced by cigarette smoke (CS) and in vitro using neutrophil chemotaxis and mast cell degranulation assays. Finally, the JME-173 pharmacokinetic profile was assessed using HPLC-MS/MS bioanalytical method. JME-173 directly inhibited IL-8 (CXCL8)- and FMLP-induced human neutrophil chemotaxis and allergen-induced mast cell degranulation. After oral administration 1 h before CS exposure, JME-173 (50 mg/kg) strongly reduced the increased number of macrophages and neutrophils recovered in the bronchoalveolar effluent without altering lymphocyte counts. Pharmacokinetic experiments of JME-173 (10 mg/kg, orally) showed values of maximum concentration (C-max), maximum time (T-max), area under the blood concentration-time curve (AUC(0-t)) and area under the blood concentration-time curve from 0-Inf (AUC(0-inf)) of 163.3 + 38.3 ng/mL, 1.2 +/- 0.3 h, 729.4 +/- 118.3 ng*h/ml and 868.9 + 117.1 ng*h/ml (means + S.E.M.), respectively. Collectively, these findings suggest that JME-173 has the potential to be an effective oral treatment for diseases associated with bronchoconstriction and inflammation.