benzyl 4'-allyl-2'-((4-carbamimidoylphenyl)carbamoyl)-4-(isobutylcarbamoyl)-[1,1'-biphenyl]-2-carboxylate | 420798-39-6

• 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: benzyl 4'-allyl-2'-((4-carbamimidoylphenyl)carbamoyl)-4-(isobutylcarbamoyl)-[1,1'-biphenyl]-2-carboxylate
• CAS: 420798-39-6
• 化学式: C₃₆H₃₆N₄O₄
• 分子量: 588.706
• InChiKey: ZNKKETRQBIXVNB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.36
• 重原子数：
  44.0
• 可旋转键数：
  12.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  134.37
• 氢给体数：
  4.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  benzyl 4'-allyl-2'-((4-carbamimidoylphenyl)carbamoyl)-4-(isobutylcarbamoyl)-[1,1'-biphenyl]-2-carboxylate 在 sodium hydroxide 、 水 作用下， 以 甲醇 为溶剂， 以69%的产率得到4'-allyl-2'-(4-carbamimidoylphenylcarbamoyl)-4-(isobutylcarbamoyl)biphenyl-2-carboxylic acid
  参考文献：
  名称：

  Design, parallel synthesis, and crystal structures of biphenyl antithrombotics as selective inhibitors of tissue factor FVIIa complex. Part 1: Exploration of S2 pocket pharmacophores

  摘要：

  Factor VIIa (FVIIa), a serine protease enzyme, coupled with tissue factor (TF) plays an important role in a number of thrombosis-related disorders. Inhibition of TF.FVIIa occurs early in the coagulation cascade and might provide some safety advantages over other related enzymes. We report here a novel series of substituted biphenyl derivatives that are highly potent and selective TF.FVIIa inhibitors. Parallel synthesis coupled with structure-based drug design allowed us to explore the S2 pocket of the enzyme active site. A number of compounds with IC50 value of <10 nM were synthesized. The X-ray crystal structures of some of these compounds complexed with TF.FVIIa were determined and results were applied to design the next round of inhibitors. All the potent inhibitors were tested for inhibition against a panel of related enzymes and selectivity of 17,600 over thrombin, 450 over trypsin, 685 over FXa, and 76 over plasmin was achieved. Two groups, vinyl 36b and 2-furan 36ab, were identified as the optimum binding substituents on the phenyl ring in the S2 pocket. Compounds with these two substituents are the most potent compounds in this series with good selectivity over related serine proteases. These compounds will be further explored for structure-activity relationship. (C) 2009 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2009.04.013
• 作为产物：
  描述：

  4-allyl-2'-((benzyloxy)carbonyl)-4'-(isobutylcarbamoyl)-[1,1'-biphenyl]-2-carboxylic acid 、 4-氨基苯甲脒 在 吡啶 、 N,N'-二环己基碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 16.0h， 以96%的产率得到benzyl 4'-allyl-2'-((4-carbamimidoylphenyl)carbamoyl)-4-(isobutylcarbamoyl)-[1,1'-biphenyl]-2-carboxylate
  参考文献：
  名称：

  Design, parallel synthesis, and crystal structures of biphenyl antithrombotics as selective inhibitors of tissue factor FVIIa complex. Part 1: Exploration of S2 pocket pharmacophores

  摘要：

  Factor VIIa (FVIIa), a serine protease enzyme, coupled with tissue factor (TF) plays an important role in a number of thrombosis-related disorders. Inhibition of TF.FVIIa occurs early in the coagulation cascade and might provide some safety advantages over other related enzymes. We report here a novel series of substituted biphenyl derivatives that are highly potent and selective TF.FVIIa inhibitors. Parallel synthesis coupled with structure-based drug design allowed us to explore the S2 pocket of the enzyme active site. A number of compounds with IC50 value of <10 nM were synthesized. The X-ray crystal structures of some of these compounds complexed with TF.FVIIa were determined and results were applied to design the next round of inhibitors. All the potent inhibitors were tested for inhibition against a panel of related enzymes and selectivity of 17,600 over thrombin, 450 over trypsin, 685 over FXa, and 76 over plasmin was achieved. Two groups, vinyl 36b and 2-furan 36ab, were identified as the optimum binding substituents on the phenyl ring in the S2 pocket. Compounds with these two substituents are the most potent compounds in this series with good selectivity over related serine proteases. These compounds will be further explored for structure-activity relationship. (C) 2009 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2009.04.013