1-(tert-butoxycarbonyl)-N-[5-chloro-2-(1H-tetrazol-1-yl)benzyl]-4,4-difluoro-L-prolinamide | 681128-16-5

• 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: 1-(tert-butoxycarbonyl)-N-[5-chloro-2-(1H-tetrazol-1-yl)benzyl]-4,4-difluoro-L-prolinamide
• 英文别名: tert-butyl (2S)-2-[[5-chloro-2-(tetrazol-1-yl)phenyl]methylcarbamoyl]-4,4-difluoropyrrolidine-1-carboxylate
• CAS: 681128-16-5
• 化学式: C₁₈H₂₁ClF₂N₆O₃
• 分子量: 442.853
• InChiKey: ALLPVGGIYUZKKB-AWEZNQCLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  30
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  102
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  1-(tert-butoxycarbonyl)-N-[5-chloro-2-(1H-tetrazol-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 1,4-二氧六环 、 二氯甲烷 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 19.0h， 生成 3-(1-methylcyclopropyl)-D-alanyl-N-[5-chloro-2-(1H-tetrazol-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-2-四唑-1-基-苄胺 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 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 以88%的产率得到1-(tert-butoxycarbonyl)-N-[5-chloro-2-(1H-tetrazol-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

文献信息

• [EN] THROMBIN INHIBITORS<br/>[FR] INHIBITEURS DE THROMBINE
  申请人：MERCK & CO INC

  公开号：WO2004032834A2

  公开（公告）日：2004-04-22

  Compounds of the invention (Formula I) are useful in inhibiting thrombin and associated thrombotic occlusions having the following structure: I.The compounds are useful for preventing or treating unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation, ocular build up of fibrin, and reocclusion or restenosis of recanalized vessels, in a mammal.
• Discovery of potent, selective 4-fluoroproline-based thrombin inhibitors with improved metabolic stability
  作者：Donnette D. Staas、Kelly L. Savage、Vanessa L. Sherman、Heidi L. Shimp、Terry A. Lyle、Lekhanh O. Tran、Catherine M. Wiscount、Daniel R. McMasters、Philip E.J. Sanderson、Peter D. Williams、Bobby J. Lucas、Julie A. Krueger、S. Dale Lewis、Rebecca B. White、Sean Yu、Bradley K. Wong、Christopher J. Kochansky、M. Reza Anari、Youwei Yan、Joseph P. Vacca

  DOI：10.1016/j.bmc.2006.06.040

  日期：2006.10

  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.