{[4-({2-[6-(3-Amino-phenyl)-5-chloro-3-cyclobutylamino-2-oxo-2H-pyrazin-1-yl]-acetylamino}-methyl)-phenyl]-imino-methyl}-carbamic acid benzyl ester | 748761-41-3

• 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: {[4-({2-[6-(3-Amino-phenyl)-5-chloro-3-cyclobutylamino-2-oxo-2H-pyrazin-1-yl]-acetylamino}-methyl)-phenyl]-imino-methyl}-carbamic acid benzyl ester
• 英文别名: benzyl N-[4-[[[2-[2-(3-aminophenyl)-3-chloro-5-(cyclobutylamino)-6-oxopyrazin-1-yl]acetyl]amino]methyl]benzenecarboximidoyl]carbamate
• CAS: 748761-41-3
• 化学式: C₃₂H₃₂ClN₇O₄
• 分子量: 614.104
• InChiKey: XGGZTJVVKVEPKO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  44
• 可旋转键数：
  11
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  165
• 氢给体数：
  4
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  {[4-({2-[6-(3-Amino-phenyl)-5-chloro-3-cyclobutylamino-2-oxo-2H-pyrazin-1-yl]-acetylamino}-methyl)-phenyl]-imino-methyl}-carbamic acid benzyl ester 在 三甲基氯硅烷 、 sodium iodide 作用下， 以 乙腈 为溶剂， 生成 2-[6-(3-Amino-phenyl)-5-chloro-3-cyclobutylamino-2-oxo-2H-pyrazin-1-yl]-N-(4-carbamimidoyl-benzyl)-acetamide
  参考文献：
  名称：

  Structure-based drug design of pyrazinone antithrombotics as selective inhibitors of the tissue factor VIIa complex

  摘要：

  Structure-based drug design coupled with polymer-assisted solution-phase library synthesis was utilized to develop a series of pyrazinone inhibitors of the tissue factor/Factor Vila complex. The crystal structure of a tri-peptide ketothiazole complexed with TF/VIIa was utilized in a docking experiment that identified a benzyl-substituted pyrazinone as a P-2 surrogate for the tri-peptide. A 5-step PASP library synthesis of these aryl-substituted pyrazinones was developed. The sequence allows for attachment of a variety of P-1 and P-3 moieties, which led to synthesis pyrazinone 23. Compound 23 exhibited 16 nM IC50 against TF/VIIa with > 6250x selectivity versus Factor Xa and thrombin. This potent and highly selective inhibitor of TF/VIIa was chosen for preclinical intravenous proof-of-concept studies to demonstrate the separation between antithrombotic efficacy and bleeding side effects in a primate model of thrombosis. (C) 2003 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(03)00410-4
• 作为产物：
  描述：

  [5-Chloro-3-cyclobutylamino-6-(3-nitro-phenyl)-2-oxo-2H-pyrazin-1-yl]-acetic acid benzyl ester 在 palladium on activated charcoal polymer-bound carbodiimide 、 氢气 、 1-羟基苯并三唑 作用下， 以 甲醇 为溶剂， 生成 {[4-({2-[6-(3-Amino-phenyl)-5-chloro-3-cyclobutylamino-2-oxo-2H-pyrazin-1-yl]-acetylamino}-methyl)-phenyl]-imino-methyl}-carbamic acid benzyl ester
  参考文献：
  名称：

  Structure-based drug design of pyrazinone antithrombotics as selective inhibitors of the tissue factor VIIa complex

  摘要：

  Structure-based drug design coupled with polymer-assisted solution-phase library synthesis was utilized to develop a series of pyrazinone inhibitors of the tissue factor/Factor Vila complex. The crystal structure of a tri-peptide ketothiazole complexed with TF/VIIa was utilized in a docking experiment that identified a benzyl-substituted pyrazinone as a P-2 surrogate for the tri-peptide. A 5-step PASP library synthesis of these aryl-substituted pyrazinones was developed. The sequence allows for attachment of a variety of P-1 and P-3 moieties, which led to synthesis pyrazinone 23. Compound 23 exhibited 16 nM IC50 against TF/VIIa with > 6250x selectivity versus Factor Xa and thrombin. This potent and highly selective inhibitor of TF/VIIa was chosen for preclinical intravenous proof-of-concept studies to demonstrate the separation between antithrombotic efficacy and bleeding side effects in a primate model of thrombosis. (C) 2003 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(03)00410-4

文献信息

• Structure-based drug design of pyrazinone antithrombotics as selective inhibitors of the tissue factor VIIa complex
  作者：Michael S. South、Brenda L. Case、Rhonda S. Wood、Darin E. Jones、Michael J. Hayes、Thomas J. Girard、Rhonda M. Lachance、Nancy S. Nicholson、Michael Clare、Anna M. Stevens、Roderick A. Stegeman、William C. Stallings、Ravi G. Kurumbail、John J. Parlow

  DOI：10.1016/s0960-894x(03)00410-4

  日期：2003.7

  Structure-based drug design coupled with polymer-assisted solution-phase library synthesis was utilized to develop a series of pyrazinone inhibitors of the tissue factor/Factor Vila complex. The crystal structure of a tri-peptide ketothiazole complexed with TF/VIIa was utilized in a docking experiment that identified a benzyl-substituted pyrazinone as a P-2 surrogate for the tri-peptide. A 5-step PASP library synthesis of these aryl-substituted pyrazinones was developed. The sequence allows for attachment of a variety of P-1 and P-3 moieties, which led to synthesis pyrazinone 23. Compound 23 exhibited 16 nM IC50 against TF/VIIa with > 6250x selectivity versus Factor Xa and thrombin. This potent and highly selective inhibitor of TF/VIIa was chosen for preclinical intravenous proof-of-concept studies to demonstrate the separation between antithrombotic efficacy and bleeding side effects in a primate model of thrombosis. (C) 2003 Elsevier Science Ltd. All rights reserved.