4-chloro-6-(3,4-dichlorophenoxy)pyrimidine

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 4-chloro-6-(3,4-dichlorophenoxy)pyrimidine
• 英文别名: 4-(3,4-Dichlorophenoxy)-6-chloropyrimidine
• 化学式: C₁₀H₅Cl₃N₂O
• mdl: MFCD14587469
• 分子量: 275.521
• InChiKey: NAICKMPKBRBVPM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  35
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  4-chloro-6-(3,4-dichlorophenoxy)pyrimidine 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 三乙胺 、 sodium hydroxide 作用下， 以 四氢呋喃 为溶剂， 20.0~50.0 ℃ 、500.01 kPa 条件下， 反应 34.0h， 生成 6-(3,4-dichlorophenoxy)pyrimidine-4-carboxylic acid
  参考文献：
  名称：

  Development of a Series of Aryl Pyrimidine Kynurenine Monooxygenase Inhibitors as Potential Therapeutic Agents for the Treatment of Huntington’s Disease

  摘要：

  We report on the development of a series of pyrimidine carboxylic acids that are potent and selective inhibitors of kynurenine monooxygenase and competitive for kynurenine. We describe the SAR for this novel series and report on their inhibition of KMO activity in biochemical and cellular assays and their selectivity against other kynurenine pathway enzymes. We describe the optimization process that led to the identification of a program lead compound with a suitable ADME/PK profile for therapeutic development. We demonstrate that systemic inhibition of KMO in vivo with this lead compound provides pharmacodynamic evidence for modulation of kynurenine pathway metabolites both in the periphery and in the central nervous system.

  DOI：

  10.1021/jm501350y
• 作为产物：
  描述：

  4,6-二氯嘧啶 、 3,4-二氯苯酚 在 potassium tert-butylate 作用下， 以 叔丁醇 为溶剂， 反应 2.08h， 以37%的产率得到4-chloro-6-(3,4-dichlorophenoxy)pyrimidine
  参考文献：
  名称：

  Development of a Series of Aryl Pyrimidine Kynurenine Monooxygenase Inhibitors as Potential Therapeutic Agents for the Treatment of Huntington’s Disease

  摘要：

  We report on the development of a series of pyrimidine carboxylic acids that are potent and selective inhibitors of kynurenine monooxygenase and competitive for kynurenine. We describe the SAR for this novel series and report on their inhibition of KMO activity in biochemical and cellular assays and their selectivity against other kynurenine pathway enzymes. We describe the optimization process that led to the identification of a program lead compound with a suitable ADME/PK profile for therapeutic development. We demonstrate that systemic inhibition of KMO in vivo with this lead compound provides pharmacodynamic evidence for modulation of kynurenine pathway metabolites both in the periphery and in the central nervous system.

  DOI：

  10.1021/jm501350y

文献信息

• Development of a Series of Aryl Pyrimidine Kynurenine Monooxygenase Inhibitors as Potential Therapeutic Agents for the Treatment of Huntington’s Disease
  作者：Leticia M. Toledo-Sherman、Michael E. Prime、Ladislav Mrzljak、Maria G. Beconi、Alan Beresford、Frederick A. Brookfield、Christopher J. Brown、Isabell Cardaun、Stephen M. Courtney、Ulrike Dijkman、Estelle Hamelin-Flegg、Peter D. Johnson、Valerie Kempf、Kathy Lyons、Kimberly Matthews、William L. Mitchell、Catherine O’Connell、Paula Pena、Kendall Powell、Arash Rassoulpour、Laura Reed、Wolfgang Reindl、Suganathan Selvaratnam、Weslyn Ward Friley、Derek A. Weddell、Naomi E. Went、Patricia Wheelan、Christin Winkler、Dirk Winkler、John Wityak、Christopher J. Yarnold、Dawn Yates、Ignacio Munoz-Sanjuan、Celia Dominguez

  DOI：10.1021/jm501350y

  日期：2015.2.12

  We report on the development of a series of pyrimidine carboxylic acids that are potent and selective inhibitors of kynurenine monooxygenase and competitive for kynurenine. We describe the SAR for this novel series and report on their inhibition of KMO activity in biochemical and cellular assays and their selectivity against other kynurenine pathway enzymes. We describe the optimization process that led to the identification of a program lead compound with a suitable ADME/PK profile for therapeutic development. We demonstrate that systemic inhibition of KMO in vivo with this lead compound provides pharmacodynamic evidence for modulation of kynurenine pathway metabolites both in the periphery and in the central nervous system.