(R)-N-[2-(2,6-dimethylphenoxy)-1-methylethyl]hydroxylamine

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: (R)-N-[2-(2,6-dimethylphenoxy)-1-methylethyl]hydroxylamine
• 英文别名: (R)-N-hydroxymexiletine；N-Hydroxy-(R)-Mexiletine；N-[(2R)-1-(2,6-dimethylphenoxy)propan-2-yl]hydroxylamine
• 化学式: C₁₁H₁₇NO₂
• 分子量: 195.261
• InChiKey: ABMUWCMGKRQAIK-SNVBAGLBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  14
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  41.5
• 氢给体数：
  2
• 氢受体数：
  3

ADMET

代谢

(R)-(-)-美西律，N-羟基的已知人体代谢物包括 (2S,3S,4S,5R)-6-[[(2R)-1-(2,6-二甲基苯氧基)丙烷-2-基]氨基]氧基-3,4,5-三羟基氧杂环己烷-2-羧酸。

(R)-(-)-Mexiletine, N-hydroxy has known human metabolites that include (2S,3S,4S,5R)-6-[[(2R)-1-(2,6-dimethylphenoxy)propan-2-yl]amino]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid.

来源:NORMAN Suspect List Exchange

反应信息

• 作为产物：
  描述：

  (2R)-1-(2,6-二甲基苯氧基)-2-丙氯化铵 在 magnesium chloride human liver microsomes 、 烟酰胺腺嘌呤双核苷酸磷酸盐 、 glucose 6-phosphate dehydrogenase 作用下， 以 水 为溶剂， 反应 0.25h， 生成 (R)-N-[2-(2,6-dimethylphenoxy)-1-methylethyl]hydroxylamine
  参考文献：
  名称：

  Role of specific cytochrome P450 enzymes in the N-oxidation of the antiarrhythmic agent mexiletine

  摘要：

  1. Mexiletine is extensively metabolized in man by C- and N-oxidation and the aim of the present study was to characterize major cytochrome P450 enzyme(s) involved in the formation of N-hydroxymexiletine.2. Incubations with genetically engineered microsomes indicated that the formation rate of N-hydroxymexiletine was highest in the presence of microsomes expressing high levels of either CYP1A2 or CYP2E1 and the formation of N-hydroxymexiletine by human liver microsomes was inhibited about 40% by antibodies directed against CYP1A1/1A2 or CYP2E1. Additional incubations demonstrated that formation of N-hydroxymexiletine was decreased 47 and 51% by furafylline, 40 muM and 120 muM, respectively, and decreased 55 and 67% by alpha-naphthoflavone, 1 muM and 3 muM, respectively (all p<0.05 versus control).3. The formation rate of N-hydroxymexiletine in human liver microsomes was highly correlated with CYP2B6 (RS-mexiletine, r=0.7827; R-(-)-enantiomer, r=0.7034; S-(+)-enantiomer, r=0.7495), CYP2E1 (S-(+)-enantiomer, r=0.7057) and CYP1A2 (RS-mexiletine, r=0.5334; S-(+)-enantiomer, r=0.6035).4. In conclusion, we have demonstrated that CYP1A2 is a major human cytochrome P450 enzyme involved in the formation of N-hydroxymexiletine. However, other cytochrome P450 enzymes (CYP2E1 and CYP2136) also appear to play a role in the N-oxidation of this drug.

  DOI：

  10.1080/0049825021000017948

文献信息

• Role of specific cytochrome P450 enzymes in the N-oxidation of the antiarrhythmic agent mexiletine
  作者：L. LabbÈ、Z. Abolfathi、È. Lessard、H. Pakdel、P. Beaune、J. Turgeon

  DOI：10.1080/0049825021000017948

  日期：2003.1

  1. Mexiletine is extensively metabolized in man by C- and N-oxidation and the aim of the present study was to characterize major cytochrome P450 enzyme(s) involved in the formation of N-hydroxymexiletine.2. Incubations with genetically engineered microsomes indicated that the formation rate of N-hydroxymexiletine was highest in the presence of microsomes expressing high levels of either CYP1A2 or CYP2E1 and the formation of N-hydroxymexiletine by human liver microsomes was inhibited about 40% by antibodies directed against CYP1A1/1A2 or CYP2E1. Additional incubations demonstrated that formation of N-hydroxymexiletine was decreased 47 and 51% by furafylline, 40 muM and 120 muM, respectively, and decreased 55 and 67% by alpha-naphthoflavone, 1 muM and 3 muM, respectively (all p<0.05 versus control).3. The formation rate of N-hydroxymexiletine in human liver microsomes was highly correlated with CYP2B6 (RS-mexiletine, r=0.7827; R-(-)-enantiomer, r=0.7034; S-(+)-enantiomer, r=0.7495), CYP2E1 (S-(+)-enantiomer, r=0.7057) and CYP1A2 (RS-mexiletine, r=0.5334; S-(+)-enantiomer, r=0.6035).4. In conclusion, we have demonstrated that CYP1A2 is a major human cytochrome P450 enzyme involved in the formation of N-hydroxymexiletine. However, other cytochrome P450 enzymes (CYP2E1 and CYP2136) also appear to play a role in the N-oxidation of this drug.