Boc-N-[5-chloro-2-(1H-1,2,4-triazol-1-yl)benzyl]-4,4-difluoro-L-prolinamide | 911831-66-8

• 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: Boc-N-[5-chloro-2-(1H-1,2,4-triazol-1-yl)benzyl]-4,4-difluoro-L-prolinamide
• CAS: 911831-66-8
• 化学式: C₁₉H₂₂ClF₂N₅O₃
• 分子量: 441.865
• InChiKey: HYKGIEWEFVYCIV-HNNXBMFYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.18
• 重原子数：
  30.0
• 可旋转键数：
  4.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  89.35
• 氢给体数：
  1.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  Boc-N-[5-chloro-2-(1H-1,2,4-triazol-1-yl)benzyl]-4,4-difluoro-L-prolinamide 在 盐酸 、 N-羟基-7-氮杂苯并三氮唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 21.0h， 生成 3-(1-methylcyclopropyl)-D-alanyl-N-[5-chloro-2-(1H-1,2,4-triazol-1-yl)benzyl]-4,4-difluoro-L-prolinamide bis(trifluoroacetate)
  参考文献：
  名称：

  Discovery of potent, selective 4-fluoroproline-based thrombin inhibitors with improved metabolic stability

  摘要：

  Previous reports from our laboratories described potent tripeptide thrombin inhibitors which incorporate heterocycle-substituted chlorophenyl groups in the PI position. Using these as lead compounds for further optimization, we identified sites of metabolism and designed analogs with 4-fluoroproline in P2 and cyclopropane-containing side chains in P3 as an approach to reducing metabolism and improving their oral pharmacokinetic performance. The large (300-fold) difference in potency between analogs containing (4R)- and (4S)-4-fluoroproline was rationalized by analyzing inhibitor-enzyme interactions in crystal structures of related compounds and by molecular modeling which indicated that the more potent (4R)-4-fluoroproline isomer stabilizes a proline ring conformation that is preferred for binding to the enzyme. An optimal compound from this work, 41, exhibits high potency in a coagulation assay in human plasma (2xAPTT = 190 nM), excellent selectivity versus the digestive enzyme trypsin (K-i = 3300 nM), and excellent oral bioavailability in dogs with moderate clearance (F = 100%, CL = 12 mL/min/kg). (c) 2006 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2006.06.040
• 作为产物：
  描述：

  N-Boc-4,4-二氟-L-脯氨酸 、 (5-氯-2-(1H-1,2,4-噻唑-1-基)苯基)甲胺 在 N-羟基-7-氮杂苯并三氮唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 18.0h， 生成 Boc-N-[5-chloro-2-(1H-1,2,4-triazol-1-yl)benzyl]-4,4-difluoro-L-prolinamide
  参考文献：
  名称：

  Discovery of potent, selective 4-fluoroproline-based thrombin inhibitors with improved metabolic stability

  摘要：

  Previous reports from our laboratories described potent tripeptide thrombin inhibitors which incorporate heterocycle-substituted chlorophenyl groups in the PI position. Using these as lead compounds for further optimization, we identified sites of metabolism and designed analogs with 4-fluoroproline in P2 and cyclopropane-containing side chains in P3 as an approach to reducing metabolism and improving their oral pharmacokinetic performance. The large (300-fold) difference in potency between analogs containing (4R)- and (4S)-4-fluoroproline was rationalized by analyzing inhibitor-enzyme interactions in crystal structures of related compounds and by molecular modeling which indicated that the more potent (4R)-4-fluoroproline isomer stabilizes a proline ring conformation that is preferred for binding to the enzyme. An optimal compound from this work, 41, exhibits high potency in a coagulation assay in human plasma (2xAPTT = 190 nM), excellent selectivity versus the digestive enzyme trypsin (K-i = 3300 nM), and excellent oral bioavailability in dogs with moderate clearance (F = 100%, CL = 12 mL/min/kg). (c) 2006 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2006.06.040