(Z)-N-{3-[5-(4-fluorophenoxy)-2-furyl]-1-methyl-2-propenyl}-N-hydroxyurea

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (Z)-N-{3-[5-(4-fluorophenoxy)-2-furyl]-1-methyl-2-propenyl}-N-hydroxyurea
• 英文别名: N-{(2Z)-3-[5-(4-fluorophenoxy)furan-2-yl]-1-methylprop-2-enyl}-N-hydroxyurea；1-[(Z)-4-[5-(4-fluorophenoxy)furan-2-yl]but-3-en-2-yl]-1-hydroxyurea
• 化学式: C₁₅H₁₅FN₂O₄
• 分子量: 306.294
• InChiKey: RTJJFGMMZKIEBW-DJWKRKHSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  22
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.13
• 拓扑面积：
  88.9
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  1-[4-[5-(4-氟苯氧基)呋喃-2-基]丁-3-炔-2-基]-1-羟基脲 在 Pd-BaSO₄ 氢气 作用下， 以 喹啉 、 乙醇 、 乙酸乙酯 为溶剂， 反应 0.5h， 以25%的产率得到(Z)-N-{3-[5-(4-fluorophenoxy)-2-furyl]-1-methyl-2-propenyl}-N-hydroxyurea
  参考文献：
  名称：

  Preparation of (R)-(+)-N-[3-[5-[(4-Fluorophenyl)methyl]-2-thienyl]-1-methyl-2-propynyl]-N-hydroxyurea (ABT-761), a second-generation 5-lipoxygenase inhibitor.

  摘要：

  Structure-activity optimization of inhibitory potency and duration of action of N-hydroxyurea containing 5-lipoxygenase inhibitors was conducted. The lipophilic heteroaryl template and the link group connnecting the template to the N-hydroxyurea pharmacophore were modified. Inhibition of 5-lipoxygenase was evaluated in vitro in a human whole blood assay. An in vitro assay using liver microsomes from monkey was used to evaluate congeners for comparative rates of glucuronidation. (3-Heteroaryl-1-methyl-2-propynyl)-N-hydroxyureas were found to be more resistant to in vitro glucuronidation. The promising inhibitor N-[3-[5-(4-fluorophenoxy)2-furyl]-1-methyl-2-propynyl]-N-hydroxyurea (6) was found to have stereoselective glucuronidation in monkey and man. The R enantiomer 7 provided longer duration of inhibition as evaluated by an ex vivo whole blood assay. Further optimization of the lipophilic template led to the discovery of (R)-(+)-N-[3-[5-[(4-fluorophenyl)methyl]-2-thienyl]-1-methyl-2-propynyl]-N-hydroxyurea (11) with more effective and prolonged inhibition of leukotriene biosynthesis than zileuton (1) and 7 in monkey and man. The optimized 5-lipoxygenase inhibitor 11 was selected for development as an investigational drug for leukotriene-mediated disorders.

  DOI：

  10.1021/jm00024a004

文献信息

• Preparation of (R)-(+)-N-[3-[5-[(4-Fluorophenyl)methyl]-2-thienyl]-1-methyl-2-propynyl]-N-hydroxyurea (ABT-761), a second-generation 5-lipoxygenase inhibitor.
  作者：Clint D. W. Brooks、Andrew O. Stewart、Anwer Basha、Pramila Bhatia、James D. Ratajczyk、Jonathan G. Martin、Richard A. Craig、Teodozyj Kolasa、Jennifer B. Bouska、Carmine Lanni、Richard R. Harris、Peter E. Malo、George W. Carter、Randy L. Bell

  DOI：10.1021/jm00024a004

  日期：1995.11

  Structure-activity optimization of inhibitory potency and duration of action of N-hydroxyurea containing 5-lipoxygenase inhibitors was conducted. The lipophilic heteroaryl template and the link group connnecting the template to the N-hydroxyurea pharmacophore were modified. Inhibition of 5-lipoxygenase was evaluated in vitro in a human whole blood assay. An in vitro assay using liver microsomes from monkey was used to evaluate congeners for comparative rates of glucuronidation. (3-Heteroaryl-1-methyl-2-propynyl)-N-hydroxyureas were found to be more resistant to in vitro glucuronidation. The promising inhibitor N-[3-[5-(4-fluorophenoxy)2-furyl]-1-methyl-2-propynyl]-N-hydroxyurea (6) was found to have stereoselective glucuronidation in monkey and man. The R enantiomer 7 provided longer duration of inhibition as evaluated by an ex vivo whole blood assay. Further optimization of the lipophilic template led to the discovery of (R)-(+)-N-[3-[5-[(4-fluorophenyl)methyl]-2-thienyl]-1-methyl-2-propynyl]-N-hydroxyurea (11) with more effective and prolonged inhibition of leukotriene biosynthesis than zileuton (1) and 7 in monkey and man. The optimized 5-lipoxygenase inhibitor 11 was selected for development as an investigational drug for leukotriene-mediated disorders.