2'-(4-carbamimidoylphenylcarbamoyl)-4'-(3-(hydroxymethyl)furan-2-yl)-4-(isobutylcarbamoyl)biphenyl-2-carboxylic acid | 420790-00-7

• 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: 2'-(4-carbamimidoylphenylcarbamoyl)-4'-(3-(hydroxymethyl)furan-2-yl)-4-(isobutylcarbamoyl)biphenyl-2-carboxylic acid
• 英文别名: Substituted biphenyl derivative, 36aq；2-[2-[(4-carbamimidoylphenyl)carbamoyl]-4-[3-(hydroxymethyl)furan-2-yl]phenyl]-5-(2-methylpropylcarbamoyl)benzoic acid
• CAS: 420790-00-7
• 化学式: C₃₁H₃₀N₄O₆
• 分子量: 554.602
• InChiKey: GFQUGBZAHVGALJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  41
• 可旋转键数：
  10
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.16
• 拓扑面积：
  179
• 氢给体数：
  6
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  methyl 2-[2-[(4-carbamimidoylphenyl)carbamoyl]-4-[3-(hydroxymethyl)furan-2-yl]phenyl]-5-(2-methylpropylcarbamoyl)benzoate 在 sodium hydroxide 、 水 作用下， 以 甲醇 为溶剂， 生成 2'-(4-carbamimidoylphenylcarbamoyl)-4'-(3-(hydroxymethyl)furan-2-yl)-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

文献信息

• Biaryl compounds as serine protease inhibitors
  申请人：BIOCRYST PHARMACEUTICALS, INC.

  公开号：US20040162281A1

  公开（公告）日：2004-08-19

  Compounds of formula (I) are useful as inhibitors of trypsin like serine protease enzymes such as thrombin, factor VIIa, factor Xa, TF/FVIIa, and trypsin. These compounds could be useful to treat and/or prevent clotting disorders, and as anticoagulating agents.

  式(I)的化合物可作为抑制类似胰蛋白酶的丝氨酸蛋白酶酶如凝血酶、第VIIa因子、第Xa因子、TF/FVIIa和胰蛋白酶的有用工具。这些化合物可用于治疗和/或预防凝血障碍，并作为抗凝血剂。
• BIARYL COMPOUNDS AS SERINE PROTEASE INHIBITORS
  申请人：Biocryst Pharmaceuticals, Inc.

  公开号：EP1383731A1

  公开（公告）日：2004-01-28
• EP1383731A4
  申请人：——

  公开号：EP1383731A4

  公开（公告）日：2005-09-28
• US6699994B1
  申请人：——

  公开号：US6699994B1

  公开（公告）日：2004-03-02
• US6936719B2
  申请人：——

  公开号：US6936719B2

  公开（公告）日：2005-08-30