N-benzyloxycarbonyl-(4S)-fluoro-L-proline n-butylamide | 185212-86-6

• 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: N-benzyloxycarbonyl-(4S)-fluoro-L-proline n-butylamide
• 英文别名: benzyl (2S,4S)-2-(butylcarbamoyl)-4-fluoropyrrolidine-1-carboxylate
• CAS: 185212-86-6
• 化学式: C₁₇H₂₃FN₂O₃
• 分子量: 322.38
• InChiKey: AVUYKUXNBVSJND-GJZGRUSLSA-N

物化性质

• 沸点：
  506.3±50.0 °C(Predicted)
• 密度：
  1.18±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  23
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  58.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  N-benzyloxycarbonyl-(4S)-fluoro-L-proline n-butylamide 在 palladium on activated charcoal 氢气 作用下， 以 甲醇 为溶剂， 25.0 ℃ 、206.84 kPa 条件下， 反应 3.0h， 以88.5%的产率得到(4S)-fluoro-L-proline n-butylamide
  参考文献：
  名称：

  Inhibitors of Tripeptidyl Peptidase II. 3. Derivation of Butabindide by Successive Structure Optimizations Leading to a Potential General Approach to Designing Exopeptidase Inhibitors

  摘要：

  The cholecystokinin-8 (CCK-8)-inactivating peptidase is a serine peptidase that has been shown to be a membrane-bound isoform of tripeptidyl peptidase II (EC 3.4.14.10). It cleaves the neurotransmitter CCK-8 sulfate at the Met-Gly bond to give Asp-Tyr(SO(3)H)-Met-OH + GlyTrp-Met-Asp-Phe-NH(2). Starting from Val-Pro-NHBu, a dipeptide of submicromolar affinity that had previously been generated to serve as a lead, successive optimization at P3, P1, and then P2 gave Abu-Pro-NHBu (18, K(i) = 80 nM). Further transformation (by making a benzologue) gave the indoline analogue, butabindide (33) as a reversible inhibitor having nanomolar affinity (Ki = 7 nM). Retrospective analysis suggested the possibility of a general approach to designing exopeptidase inhibitors starting from the structure of the first hydrolysis product. Application of this approach to CCK-8 led to Abu-Phe-NHBu (37), but this only had K(i) = 9.4 mu M. Molecular modeling, to determine the minimum energy conformations and explain the 1000-fold better affinity of butabindide, indicated that 37 cannot access the likely active conformation of butabindide.

  DOI：

  10.1021/jm0500830
• 作为产物：
  描述：

  (2S,4S)-4-氟-1,2-吡咯烷二羧酸 2-甲基 1-(苯基甲基)酯 在 N-乙基吗啉 、 sodium hydroxide 、 氯甲酸异丁酯 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 18.5h， 生成 N-benzyloxycarbonyl-(4S)-fluoro-L-proline n-butylamide
  参考文献：
  名称：

  Inhibitors of Tripeptidyl Peptidase II. 3. Derivation of Butabindide by Successive Structure Optimizations Leading to a Potential General Approach to Designing Exopeptidase Inhibitors

  摘要：

  The cholecystokinin-8 (CCK-8)-inactivating peptidase is a serine peptidase that has been shown to be a membrane-bound isoform of tripeptidyl peptidase II (EC 3.4.14.10). It cleaves the neurotransmitter CCK-8 sulfate at the Met-Gly bond to give Asp-Tyr(SO(3)H)-Met-OH + GlyTrp-Met-Asp-Phe-NH(2). Starting from Val-Pro-NHBu, a dipeptide of submicromolar affinity that had previously been generated to serve as a lead, successive optimization at P3, P1, and then P2 gave Abu-Pro-NHBu (18, K(i) = 80 nM). Further transformation (by making a benzologue) gave the indoline analogue, butabindide (33) as a reversible inhibitor having nanomolar affinity (Ki = 7 nM). Retrospective analysis suggested the possibility of a general approach to designing exopeptidase inhibitors starting from the structure of the first hydrolysis product. Application of this approach to CCK-8 led to Abu-Phe-NHBu (37), but this only had K(i) = 9.4 mu M. Molecular modeling, to determine the minimum energy conformations and explain the 1000-fold better affinity of butabindide, indicated that 37 cannot access the likely active conformation of butabindide.

  DOI：

  10.1021/jm0500830

文献信息

• Tripeptidylpeptidase inhibitors
  申请人：INSERM

  公开号：US20030027743A1

  公开（公告）日：2003-02-06

  A compound of the formula 1 wherein the substituents are defined as in the specification and salts or hydrates thereof is disclosed as well as a method of treating disorders associated with the inactivation or excessive degradation of cholecystokinin.

  本发明揭示了式1的化合物，其中置换基如规范中所定义，以及其盐或水合物，以及一种治疗与胆囊收缩素失活或过度降解相关的疾病的方法。
• INHIBITEURS DE TRIPEPTIDYLPEPTIDASES
  申请人：INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE (INSERM)

  公开号：EP0828851B1

  公开（公告）日：2005-07-20
• US6403561B1
  申请人：——

  公开号：US6403561B1

  公开（公告）日：2002-06-11
• Inhibitors of Tripeptidyl Peptidase II. 3. Derivation of Butabindide by Successive Structure Optimizations Leading to a Potential General Approach to Designing Exopeptidase Inhibitors
  作者：C. Robin Ganellin、Paul B. Bishop、Ramesh B. Bambal、Suzanne M. T. Chan、Bertrand Leblond、Andrew N. J. Moore、Lihua Zhao、Pierre Bourgeat、Christiane Rose、Froylan Vargas、Jean-Charles Schwartz

  DOI：10.1021/jm0500830

  日期：2005.11.1

  The cholecystokinin-8 (CCK-8)-inactivating peptidase is a serine peptidase that has been shown to be a membrane-bound isoform of tripeptidyl peptidase II (EC 3.4.14.10). It cleaves the neurotransmitter CCK-8 sulfate at the Met-Gly bond to give Asp-Tyr(SO(3)H)-Met-OH + GlyTrp-Met-Asp-Phe-NH(2). Starting from Val-Pro-NHBu, a dipeptide of submicromolar affinity that had previously been generated to serve as a lead, successive optimization at P3, P1, and then P2 gave Abu-Pro-NHBu (18, K(i) = 80 nM). Further transformation (by making a benzologue) gave the indoline analogue, butabindide (33) as a reversible inhibitor having nanomolar affinity (Ki = 7 nM). Retrospective analysis suggested the possibility of a general approach to designing exopeptidase inhibitors starting from the structure of the first hydrolysis product. Application of this approach to CCK-8 led to Abu-Phe-NHBu (37), but this only had K(i) = 9.4 mu M. Molecular modeling, to determine the minimum energy conformations and explain the 1000-fold better affinity of butabindide, indicated that 37 cannot access the likely active conformation of butabindide.