S(-)-A-79176

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: S(-)-A-79176
• 英文别名: 1-[(2S)-4-[5-(4-fluorophenoxy)furan-2-yl]but-3-yn-2-yl]-1-hydroxyurea
• 化学式: C₁₅H₁₃FN₂O₄
• 分子量: 304.278
• InChiKey: OLZHFFKRBCZHHT-JTQLQIEISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  22
• 可旋转键数：
  4
• 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 生成 S(-)-A-79176
  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

• [EN] (S)-(-)-N-[3- [5-(4-FLUOROPHENOXY) -2-FURANYL]-1-METHYL -2-PROPYNYL]-N-HYDROXYUREA<br/>[FR] (S)-(-)-N-[3- [5-(4-FLUOROPHENOXY) -2-FURANYL]-1-METHYL -2-PROPYNYL]-N-HYDROXYUREE
  申请人：SEPRACOR, INC.

  公开号：WO1998058644A1

  公开（公告）日：1998-12-30

  (EN) Methods utilizing optically pure A-79176 for the treatment of asthma, allergic rhinitis, psoriasis and inflammatory bowel disease while substantially reducing the concomitant liability of adverse effects associated with the corresponding R enantiomer and the racemic mixture. A-79176 is an inhibitor of 5-lipoxygenase and is therefore useful in the treatment of other conditions related to elevated leukotriene levels. Its structure is (I).(FR) L'invention concerne des procédés d'utilisation du A-79176 optiquement pur afin de traiter l'asthme, la rhinite allergique, le psoriasis, et les maladies intestinales inflammatoires, tout en réduisant sensiblement le risque concomitant d'effets nocifs liés à l'énantiomère R correspondant et au mélange racémique. En tant qu'inhibiteur de la 5-lipoxygenase, le A-79176 est utile au traitement d'autres désordres liés à des niveaux élevés de leucotriène. La structure de cet inhibiteur est (I).
• [EN] (S)-(-)-N-[3- [5-[(4-FLUOROPHENYL)METHYL] -2-THIENYL]-1-METHYL -2-PROPYNYL]-N-HYDROXYUREA<br/>[FR] (S)-(-)-N-[3- [5-[(4-FLUOROPHENYL)METHYL] -2-THIENYL]-1-METHYL -2-PROPYNYL]-N-HYDROXYUREE
  申请人：SEPRACOR, INC.

  公开号：WO1998058645A1

  公开（公告）日：1998-12-30

  (EN) Methods utilizing optically pure S761 for the treatment of asthma, allergic rhinitis, psoriasis and inflammatory bowel disease while substantially reducing the concomitant liability of adverse effects associated with the corresponding R enantiomer and the racemic mixture. S761 is an inhibitor of 5-lipoxygenase and is therefore useful in the treatment of other conditions related to elevated leukotriene levels. Its structure is formula (I).(FR) Procédés d'utilisation de S761 optiquement pure pour le traitement de l'asthme, de la rhinite allergique, du psoriasis et des infections inflammatoires du tube digestif, qui permet parallèlement de réduire considérablement les effets secondaires associés à l'énantiomère R correspondant et au mélange racémique. La S761, qui est un inhibiteur de la 5-lipoxygénase, est par conséquent utile dans le traitement d'autres états pathologiques associés à des taux élevés de leucotriène. Elle possède une structure de formule (I).
• 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.