[3,5-Dichloro-6-(2-chloro-phenyl)-2-oxo-2H-pyrazin-1-yl]-acetic acid benzyl ester | 609345-97-3

• 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: [3,5-Dichloro-6-(2-chloro-phenyl)-2-oxo-2H-pyrazin-1-yl]-acetic acid benzyl ester
• 英文别名: Benzyl 2-[3,5-dichloro-2-(2-chlorophenyl)-6-oxopyrazin-1-yl]acetate
• CAS: 609345-97-3
• 化学式: C₁₉H₁₃Cl₃N₂O₃
• 分子量: 423.683
• InChiKey: GTEXAOJFYQSVBD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  27
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  59
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  [3,5-Dichloro-6-(2-chloro-phenyl)-2-oxo-2H-pyrazin-1-yl]-acetic acid benzyl ester 在 氢氧化钾 、 polymer-bound carbodiimide reagent 、 1-羟基苯并三唑 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 3.0h， 生成 [1-Amino-1-[4-({2-[5-chloro-6-(2-chloro-phenyl)-2-oxo-3-phenethylamino-2H-pyrazin-1-yl]-acetylamino}-methyl)-phenyl]-meth-(Z)-ylidene]-carbamic acid benzyl ester
  参考文献：
  名称：

  Design, Parallel Synthesis, and Crystal Structures of Pyrazinone Antithrombotics as Selective Inhibitors of the Tissue Factor VIIa Complex

  摘要：

  Structure-based drug design (SBDD) and polymer-assisted solution-phase (PASP) library synthesis were used to develop a series of pyrazinone inhibitors of the Tissue Factor/Factor Vlla (TF/VIIa) complex. The crystal structure of a tripeptide-alpha-ketothiazole complexed with TF/VIIa was utilized in a docking experiment to identify the pyrazinone core as a starting scaffold. The pyrazinone core could orient the substituents in the correct spatial arrangement to probe the S-1, S-2, and S-3 pockets of the enzyme. A multistep PASP library synthesis was designed to prepare the substituted pyrazinones varying the P-1, P-2, and P-3 moieties. Hundreds of pyrazinone TF/VIIa inhibitors were prepared and tested in several serine protease enzyme assays involved in the coagulation cascade. The inhibitors exhibited modest activity on TF/ VIIa with excellent selectivity over thrombin (Ha) and Factor Xa. The structure-activity relationship of the pyrazinone inhibitors will be discussed and X-ray crystal structures of selected compounds complexed with the TF/VIIa enzyme will be described. This study ultimately led to the synthesis of compound 34, which exhibited 16 nM (IC50) activity on TF/VIIa with >6250x selectivity vs 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 nonhuman primate model of electrolytic-induced arterial thrombosis.

  DOI：

  10.1021/jm030131l
• 作为产物：
  描述：

  草酰氯 、 三甲基氰硅烷 、 甘氨酸苄酯盐酸盐 、 2-氯苯甲醛 以 二氯甲烷 、 邻二氯苯 为溶剂， 生成 [3,5-Dichloro-6-(2-chloro-phenyl)-2-oxo-2H-pyrazin-1-yl]-acetic acid benzyl ester
  参考文献：
  名称：

  Design, Parallel Synthesis, and Crystal Structures of Pyrazinone Antithrombotics as Selective Inhibitors of the Tissue Factor VIIa Complex

  摘要：

  Structure-based drug design (SBDD) and polymer-assisted solution-phase (PASP) library synthesis were used to develop a series of pyrazinone inhibitors of the Tissue Factor/Factor Vlla (TF/VIIa) complex. The crystal structure of a tripeptide-alpha-ketothiazole complexed with TF/VIIa was utilized in a docking experiment to identify the pyrazinone core as a starting scaffold. The pyrazinone core could orient the substituents in the correct spatial arrangement to probe the S-1, S-2, and S-3 pockets of the enzyme. A multistep PASP library synthesis was designed to prepare the substituted pyrazinones varying the P-1, P-2, and P-3 moieties. Hundreds of pyrazinone TF/VIIa inhibitors were prepared and tested in several serine protease enzyme assays involved in the coagulation cascade. The inhibitors exhibited modest activity on TF/ VIIa with excellent selectivity over thrombin (Ha) and Factor Xa. The structure-activity relationship of the pyrazinone inhibitors will be discussed and X-ray crystal structures of selected compounds complexed with the TF/VIIa enzyme will be described. This study ultimately led to the synthesis of compound 34, which exhibited 16 nM (IC50) activity on TF/VIIa with >6250x selectivity vs 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 nonhuman primate model of electrolytic-induced arterial thrombosis.

  DOI：

  10.1021/jm030131l