methyl 3-amino-5-[1-(2-{[4-((Z)-amino{[(benzyloxy)carbonyl]imino}methyl)benzyl]amino}-2-oxoethyl)-3-chloro-5-(isopropylamino)-6-oxo-1,6-dihydropyrazin-2-yl]benzoate | 609345-95-1

• 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: methyl 3-amino-5-[1-(2-{[4-((Z)-amino{[(benzyloxy)carbonyl]imino}methyl)benzyl]amino}-2-oxoethyl)-3-chloro-5-(isopropylamino)-6-oxo-1,6-dihydropyrazin-2-yl]benzoate
• 英文别名: methyl 3-amino-5-[3-chloro-6-oxo-1-[2-oxo-2-[[4-(N-phenylmethoxycarbonylcarbamimidoyl)phenyl]methylamino]ethyl]-5-(propan-2-ylamino)pyrazin-2-yl]benzoate
• CAS: 609345-95-1
• 化学式: C₃₃H₃₄ClN₇O₆
• 分子量: 660.129
• InChiKey: YAYOKLPXCLABDG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  47
• 可旋转键数：
  13
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  191
• 氢给体数：
  4
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  methyl 3-amino-5-[1-(2-{[4-((Z)-amino{[(benzyloxy)carbonyl]imino}methyl)benzyl]amino}-2-oxoethyl)-3-chloro-5-(isopropylamino)-6-oxo-1,6-dihydropyrazin-2-yl]benzoate 在 lithium hydroxide 作用下， 以 甲醇 为溶剂， 反应 16.0h， 以34%的产率得到3-amino-5-[1-[2-({4-[amino(imino)methyl]benzyl}amino)-2-oxoethyl]-3-chloro-5-(isopropylamino)-6-oxo-1,6-dihydropyrazin-2-yl]benzoic acid
  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：

  3-(羟基甲基)-5-硝基苯甲酸甲酯 在 palladium on activated charcoal N-甲基吗啉 、 盐酸 、 草酰氯 、 polymer-bound carbodiimide reagent 、 氢气 、 1-羟基苯并三唑 、 二甲基亚砜 、 三乙胺 作用下， 以 甲醇 、 二氯甲烷 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 67.75h， 生成 methyl 3-amino-5-[1-(2-{[4-((Z)-amino{[(benzyloxy)carbonyl]imino}methyl)benzyl]amino}-2-oxoethyl)-3-chloro-5-(isopropylamino)-6-oxo-1,6-dihydropyrazin-2-yl]benzoate
  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

文献信息

• [EN] PRODRUGS OF SUBSTITUTED POLYCYCLIC COMPOUNDS USEFUL FOR SELECTIVE INHIBITION OF THE COAGULATION CASCADE<br/>[FR] PROMEDICAMENTS DE COMPOSES POLYCYCLIQUES SUBSTITUES UTILES POUR L'INHIBITION SELECTIVE DE LA CASCADE DE LA COAGULATION
  申请人：PHARMACIA CORP

  公开号：WO2003028729A2

  公开（公告）日：2003-04-10

  The present invention relates to prodrug compounds, comprising a 5- or 6- membered heterocyclic or aromatic ring substituted with a derivatized amidine, as well as compositions and methods useful for preventing and treating thrombotic conditions in mammals. The prodrug compounds of the present invention selectively inhibit certain proteases of the coagulation cascade.