[2-({[(S)-1-((R)-2-tert-Butoxycarbonylamino-2-cyclohexyl-acetyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-4-chloro-phenoxy]-acetic acid | 211989-81-0

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: [2-({[(S)-1-((R)-2-tert-Butoxycarbonylamino-2-cyclohexyl-acetyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-4-chloro-phenoxy]-acetic acid
• 英文别名: [2-({[((2S)-1-{(2R)-2-[(tert-butoxycarbonyl) amino]-2-cyclohexylethanoyl} pyrrolidin-2-yl)carbonyl]amino} methyl)-4-chlorophenoxy]acetic acid；2-[4-chloro-2-[[[(2S)-1-[(2R)-2-cyclohexyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]acetyl]pyrrolidine-2-carbonyl]amino]methyl]phenoxy]acetic acid
• CAS: 211989-81-0
• 化学式: C₂₇H₃₈ClN₃O₇
• 分子量: 552.068
• InChiKey: AEBLDBSDFOICMZ-NZQKXSOJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  38
• 可旋转键数：
  11
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.63
• 拓扑面积：
  134
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  [2-({[(S)-1-((R)-2-tert-Butoxycarbonylamino-2-cyclohexyl-acetyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-4-chloro-phenoxy]-acetic acid 在 N-甲基吗啉 、 1-羟基苯并三唑 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 18.5h， 生成 D-cyclohexylglycine-proline-N-[2-(O-ethylacetamido)-5-chlorobenzyl]amide
  参考文献：
  名称：

  Design and Synthesis of a Series of Potent and Orally Bioavailable Noncovalent Thrombin Inhibitors That Utilize Nonbasic Groups in the P1 Position

  摘要：

  As part of an ongoing effort to prepare therapeutically useful orally active thrombin inhibitors, we have synthesized a series of compounds that utilize nonbasic groups in the P1 position. The work is based on our previously reported lead structure, compound 1, which was discovered via a resin-based approach to varying P1. By minimizing the size and lipophilicity of the P3 group and by incorporating hydrogen-bonding groups on the N-terminus or on the 2-position of the P1 aromatic ring, we have prepared a number of derivatives in this series that exhibit subnanomolar enzyme potency combined with good in vivo antithrombotic and bioavailability profiles. The oxyacetic amide compound 14b exhibited the best overall profile of in vitro and in vivo activity, and crystallographic studies indicate a unique mode of binding in the thrombin active site.

  DOI：

  10.1021/jm9801713
• 作为产物：
  描述：

  Boc-D-环己基甘氨酸 在 lithium hydroxide 、 1-羟基苯并三唑 、 caesium carbonate 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 三乙胺 作用下， 以 1,4-二氧六环 、 乙二醇二甲醚 、 N,N-二甲基甲酰胺 为溶剂， 反应 72.0h， 生成 [2-({[(S)-1-((R)-2-tert-Butoxycarbonylamino-2-cyclohexyl-acetyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-4-chloro-phenoxy]-acetic acid
  参考文献：
  名称：

  Design and Synthesis of a Series of Potent and Orally Bioavailable Noncovalent Thrombin Inhibitors That Utilize Nonbasic Groups in the P1 Position

  摘要：

  As part of an ongoing effort to prepare therapeutically useful orally active thrombin inhibitors, we have synthesized a series of compounds that utilize nonbasic groups in the P1 position. The work is based on our previously reported lead structure, compound 1, which was discovered via a resin-based approach to varying P1. By minimizing the size and lipophilicity of the P3 group and by incorporating hydrogen-bonding groups on the N-terminus or on the 2-position of the P1 aromatic ring, we have prepared a number of derivatives in this series that exhibit subnanomolar enzyme potency combined with good in vivo antithrombotic and bioavailability profiles. The oxyacetic amide compound 14b exhibited the best overall profile of in vitro and in vivo activity, and crystallographic studies indicate a unique mode of binding in the thrombin active site.

  DOI：

  10.1021/jm9801713

文献信息

• Design and synthesis of potent and selective macrocyclic thrombin inhibitors
  作者：Philippe G. Nantermet、James C. Barrow、Christina L. Newton、Janetta M. Pellicore、MaryBeth Young、S.Dale Lewis、Bobby J. Lucas、Julie A. Krueger、Daniel R. McMasters、Youwei Yan、Lawrence C. Kuo、Joseph P. Vacca、Harold G. Selnick

  DOI：10.1016/s0960-894x(03)00506-7

  日期：2003.8

  A series of potent and selective proline- and pyrazinone-based macrocyclic thrombin inhibitors is described. Detailed SAR studies led to the incorporation of specific functional groups in the tether that enhanced functional activity against thrombin and provided exquisite selectivity against trypsin and tPA. X-ray crystallography and molecular modeling studies revealed the inhibitor-enzyme interactions

  描述了一系列有效的和选择性的基于脯氨酸和吡嗪酮的大环凝血酶抑制剂。详尽的SAR研究导致将特定的官能团结合到系链中，从而增强了对凝血酶的功能活性，并提供了对胰蛋白酶和tPA的出色选择性。X射线晶体学和分子模型研究表明，抑制剂与酶之间的相互作用是造成这种选择性的原因。
• Thrombin inhibitors
  申请人：——

  公开号：US20030216301A1

  公开（公告）日：2003-11-20

  Compounds of the invention are useful in inhibiting thrombin and associated thrombotic occlusions having the following structure: 1 or a pharmaceutically acceptable salt thereof.

  本发明的化合物具有以下结构，可用于抑制凝血酶及相关的血栓闭塞性病变：1或其药学上可接受的盐。