N¹-(3-(amino(hydroxyimino)methyl)benzoyl)-N²-(4-ethoxybenzoyl)-1,2-benzenediamine | 219519-99-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N¹-(3-(amino(hydroxyimino)methyl)benzoyl)-N²-(4-ethoxybenzoyl)-1,2-benzenediamine
• 英文别名: N-[2-[(4-ethoxybenzoyl)amino]phenyl]-3-(N'-hydroxycarbamimidoyl)benzamide
• CAS: 219519-99-0
• 化学式: C₂₃H₂₂N₄O₄
• 分子量: 418.452
• InChiKey: WPGMAOLLABSNAK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  31
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.09
• 拓扑面积：
  126
• 氢给体数：
  4
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  N¹-(3-(amino(hydroxyimino)methyl)benzoyl)-N²-(4-ethoxybenzoyl)-1,2-benzenediamine 在 10percent Pd/C 盐酸 、 氢气 作用下， 以 四氢呋喃 、 乙醇 为溶剂， 反应 24.0h， 生成 N¹-(3-(aminoiminomethyl)benzoyl)-N²-(4-ethoxybenzoyl)-1,2-benzenediamine hydrochloride
  参考文献：
  名称：

  Structure-Based Design of Potent, Amidine-Derived Inhibitors of Factor Xa:  Evaluation of Selectivity, Anticoagulant Activity, and Antithrombotic Activity

  摘要：

  To enhance the potency of 1,2-dibenzamidobenzene-derived inhibitors of factor Xa (fXa), an amidine substituent was incorporated on one of the benzoyl side chains to interact with Asp189 in the S1 specificity pocket. Lead molecule 1 was docked into the active site of Ma to facilitate inhibitor design. Subsequently, iterative SAR studies and molecular modeling led to a 1000-fold increase in Ma affinity and a refined model of the new inhibitors in the Ma active site. Strong support for the computational model was achieved through the acquisition of an X-ray crystal structure using thrombin as a surrogate protein. The amidines in this series show high levels of selectivity for the inhibition of Ma relative to other trypsin-like serine proteases. Furthermore, the Ma affinity of compounds in this series (K-ass = 50-500 x 10(6) L/mol) translates effectively into both anticoagulant activity in vitro and antithrombotic activity in vivo.

  DOI：

  10.1021/jm9903287
• 作为产物：
  描述：

  4-乙氧基苯甲酰氯 在 吡啶 、 盐酸羟胺 、 N,N-二异丙基乙胺 作用下， 以 乙醇 、 二氯甲烷 为溶剂， 生成 N¹-(3-(amino(hydroxyimino)methyl)benzoyl)-N²-(4-ethoxybenzoyl)-1,2-benzenediamine
  参考文献：
  名称：

  Structure-Based Design of Potent, Amidine-Derived Inhibitors of Factor Xa:  Evaluation of Selectivity, Anticoagulant Activity, and Antithrombotic Activity

  摘要：

  To enhance the potency of 1,2-dibenzamidobenzene-derived inhibitors of factor Xa (fXa), an amidine substituent was incorporated on one of the benzoyl side chains to interact with Asp189 in the S1 specificity pocket. Lead molecule 1 was docked into the active site of Ma to facilitate inhibitor design. Subsequently, iterative SAR studies and molecular modeling led to a 1000-fold increase in Ma affinity and a refined model of the new inhibitors in the Ma active site. Strong support for the computational model was achieved through the acquisition of an X-ray crystal structure using thrombin as a surrogate protein. The amidines in this series show high levels of selectivity for the inhibition of Ma relative to other trypsin-like serine proteases. Furthermore, the Ma affinity of compounds in this series (K-ass = 50-500 x 10(6) L/mol) translates effectively into both anticoagulant activity in vitro and antithrombotic activity in vivo.

  DOI：

  10.1021/jm9903287

文献信息

• Antithrombotic agents
  申请人：Eli Lilly and Company

  公开号：US06417200B1

  公开（公告）日：2002-07-09

  This application relates to a compound of formula (I), a pharmaceutically acceptable salt of the compound, or a prodrug thereof, as defined herein, pharmaceutical compositions thereof, and its use as an inhibitor of factor Xa, as well as a process for its preparation and intermediates therefor.

  这种应用涉及到式(I)的化合物，该化合物的药用盐或其前药，如本文所定义的，以及其药物组合物，以及其作为Xa因子抑制剂的用途，以及其制备方法和中间体。
• Structure-Based Design of Potent, Amidine-Derived Inhibitors of Factor Xa:  Evaluation of Selectivity, Anticoagulant Activity, and Antithrombotic Activity
  作者：Michael R. Wiley、Leonard C. Weir、Steven Briggs、Nancy A. Bryan、John Buben、Charles Campbell、Nickolay Y. Chirgadze、Richard C. Conrad、Trelia J. Craft、James V. Ficorilli、Jeffry B. Franciskovich、Larry L. Froelich、Donetta S. Gifford-Moore、Theodore Goodson、David K. Herron、Valentine J. Klimkowski、Kenneth D. Kurz、Jeffery A. Kyle、John J. Masters、Andrew M. Ratz、Guy Milot、Robert T. Shuman、Tommy Smith、Gerald F. Smith、Ann Louise Tebbe、Jennifer M. Tinsley、Richard D. Towner、Alexander Wilson、Ying K. Yee

  DOI：10.1021/jm9903287

  日期：2000.3.1

  To enhance the potency of 1,2-dibenzamidobenzene-derived inhibitors of factor Xa (fXa), an amidine substituent was incorporated on one of the benzoyl side chains to interact with Asp189 in the S1 specificity pocket. Lead molecule 1 was docked into the active site of Ma to facilitate inhibitor design. Subsequently, iterative SAR studies and molecular modeling led to a 1000-fold increase in Ma affinity and a refined model of the new inhibitors in the Ma active site. Strong support for the computational model was achieved through the acquisition of an X-ray crystal structure using thrombin as a surrogate protein. The amidines in this series show high levels of selectivity for the inhibition of Ma relative to other trypsin-like serine proteases. Furthermore, the Ma affinity of compounds in this series (K-ass = 50-500 x 10(6) L/mol) translates effectively into both anticoagulant activity in vitro and antithrombotic activity in vivo.