(2S,3S)-ethyl 3-((S)-1-oxo-1-(prop-2-ynylamino)-3-(thiazol-4-yl)propan-2-ylcarbamoyl)oxirane-2-carboxylate | 1448428-90-7

• 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: (2S,3S)-ethyl 3-((S)-1-oxo-1-(prop-2-ynylamino)-3-(thiazol-4-yl)propan-2-ylcarbamoyl)oxirane-2-carboxylate
• 英文别名: (2S,3S)-ethyl-3-((S)-1-oxo-1-(prop-2-ynylamino)-3-(thiazol-4-yl)propan-2-ylcarbamoyl)oxirane-2-carboxylate；ethyl (2S,3S)-3-[[(2S)-1-oxo-1-(prop-2-ynylamino)-3-(1,3-thiazol-4-yl)propan-2-yl]carbamoyl]oxirane-2-carboxylate
• CAS: 1448428-90-7
• 化学式: C₁₅H₁₇N₃O₅S
• 分子量: 351.383
• InChiKey: MNBPUDZWKHGOBM-SRVKXCTJSA-N

物化性质

• 沸点：
  663.9±55.0 °C(Predicted)
• 密度：
  1.380±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.1
• 重原子数：
  24
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  138
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (2S,3S)-ethyl 3-((S)-1-oxo-1-(prop-2-ynylamino)-3-(thiazol-4-yl)propan-2-ylcarbamoyl)oxirane-2-carboxylate 在 copper(II) sulfate 、 sodium ascorbate 、 lithium hydroxide 、 三[(1-苄基-1H-1,2,3-三唑-4-基)甲基]胺 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 水 、 叔丁醇 为溶剂， 反应 15.0h， 生成 (2S,3S)-3-((S)-1-oxo-1-((1-phenyl-1H-1,2,3-triazol-4-yl)methylamino)-3-(thiazol-4-yl)propan-2-ylcarbamoyl)oxirane-2-carboxylic acid
  参考文献：
  名称：

  Design, Synthesis, and Optimization of Novel Epoxide Incorporating Peptidomimetics as Selective Calpain Inhibitors

  摘要：

  Hyperactivation of the calcium-dependent cysteine protease calpain 1 (Call) is implicated as a primary or secondary pathological event in a wide range of illnesses and in neurodegenerative states, including Alzheimer's disease (AD). E-64 is an epoxide-containing natural product identified as a potent nonselective, calpain inhibitor, with demonstrated efficacy in animal models of AD. By use of E-64 as a lead, three successive generations of calpain inhibitors were developed using computationally assisted design to increase selectivity for Call. First generation analogues were potent inhibitors, effecting covalent modification of recombinant Call catalytic domain (Call(cat)), demonstrated using LC-MS/MS. Refinement yielded second generation inhibitors with improved selectivity. Further library expansion and ligand refinement gave three Call inhibitors, one of which was designed as an activity-based protein profiling probe. These were determined to be irreversible and selective inhibitors by kinetics studies comparing full length Call with the genera l cysteine protease papain.

  DOI：

  10.1021/jm4006719
• 作为产物：
  描述：

  diethyl (2S,3R)-(+)-erythro-2-hydroxy-3-bromosuccinate 在 1-羟基苯并三唑 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 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 、 potassium hydroxide 作用下， 以 乙醚 、 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 25.5h， 生成 (2S,3S)-ethyl 3-((S)-1-oxo-1-(prop-2-ynylamino)-3-(thiazol-4-yl)propan-2-ylcarbamoyl)oxirane-2-carboxylate
  参考文献：
  名称：

  Design, Synthesis, and Optimization of Novel Epoxide Incorporating Peptidomimetics as Selective Calpain Inhibitors

  摘要：

  Hyperactivation of the calcium-dependent cysteine protease calpain 1 (Call) is implicated as a primary or secondary pathological event in a wide range of illnesses and in neurodegenerative states, including Alzheimer's disease (AD). E-64 is an epoxide-containing natural product identified as a potent nonselective, calpain inhibitor, with demonstrated efficacy in animal models of AD. By use of E-64 as a lead, three successive generations of calpain inhibitors were developed using computationally assisted design to increase selectivity for Call. First generation analogues were potent inhibitors, effecting covalent modification of recombinant Call catalytic domain (Call(cat)), demonstrated using LC-MS/MS. Refinement yielded second generation inhibitors with improved selectivity. Further library expansion and ligand refinement gave three Call inhibitors, one of which was designed as an activity-based protein profiling probe. These were determined to be irreversible and selective inhibitors by kinetics studies comparing full length Call with the genera l cysteine protease papain.

  DOI：

  10.1021/jm4006719

文献信息

• Cysteine protease inhibitors and uses thereof
  申请人：The Trustees of Columbia University in the City of New York

  公开号：US09403843B2

  公开（公告）日：2016-08-02

  The invention provides for novel cysteine protease inhibitors and compositions comprising novel cysteine protease derivatives. The invention further provides for methods for treatment of neurodegenerative diseases comprising administration novel cysteine protease inhibitors or compositions comprising novel cysteine protease inhibitors. In some embodiments, the cysteine protease inhibitors are calpain inhibitors.

  该发明提供了新型半胱氨酸蛋白酶抑制剂和包含新型半胱氨酸蛋白酶衍生物的组合物。该发明还提供了用于治疗神经退行性疾病的方法，包括给予新型半胱氨酸蛋白酶抑制剂或包含新型半胱氨酸蛋白酶抑制剂的组合物。在某些实施例中，这些半胱氨酸蛋白酶抑制剂是卡尔宁抑制剂。
• Novel Cysteine Protease Inhibitors and Uses Thereof
  申请人：The Trustees of Columbia University in the city of New York

  公开号：US20150045393A1

  公开（公告）日：2015-02-12

  The invention provides for novel cysteine protease inhibitors and compositions comprising novel cysteine protease derivatives. The invention further provides for methods for treatment of neurodegenerative diseases comprising administration novel cysteine protease inhibitors or compositions comprising novel cysteine protease inhibitors. In some embodiments, the cysteine protease inhibitors are calpain inhibitors.

  该发明提供了新型半胱氨酸蛋白酶抑制剂和包含新型半胱氨酸蛋白酶衍生物的组合物。该发明还提供了治疗神经退行性疾病的方法，包括给予新型半胱氨酸蛋白酶抑制剂或包含新型半胱氨酸蛋白酶抑制剂的组合物。在某些实施例中，半胱氨酸蛋白酶抑制剂为钙蛋白酶抑制剂。
• NOVEL CYSTEINE PROTEASE INHIBITORS AND USES THEREOF
  申请人：The Trustees of Columbia University in the City of New York

  公开号：EP2811999B1

  公开（公告）日：2021-10-27
• US9403843B2
  申请人：——

  公开号：US9403843B2

  公开（公告）日：2016-08-02
• Design, Synthesis, and Optimization of Novel Epoxide Incorporating Peptidomimetics as Selective Calpain Inhibitors
  作者：Isaac T. Schiefer、Subhasish Tapadar、Vladislav Litosh、Marton Siklos、Rob Scism、Gihani T. Wijewickrama、Esala P. Chandrasena、Vaishali Sinha、Ehsan Tavassoli、Michael Brunsteiner、Mauro Fa’、Ottavio Arancio、Pavel Petukhov、Gregory R. J. Thatcher

  DOI：10.1021/jm4006719

  日期：2013.8.8

  Hyperactivation of the calcium-dependent cysteine protease calpain 1 (Call) is implicated as a primary or secondary pathological event in a wide range of illnesses and in neurodegenerative states, including Alzheimer's disease (AD). E-64 is an epoxide-containing natural product identified as a potent nonselective, calpain inhibitor, with demonstrated efficacy in animal models of AD. By use of E-64 as a lead, three successive generations of calpain inhibitors were developed using computationally assisted design to increase selectivity for Call. First generation analogues were potent inhibitors, effecting covalent modification of recombinant Call catalytic domain (Call(cat)), demonstrated using LC-MS/MS. Refinement yielded second generation inhibitors with improved selectivity. Further library expansion and ligand refinement gave three Call inhibitors, one of which was designed as an activity-based protein profiling probe. These were determined to be irreversible and selective inhibitors by kinetics studies comparing full length Call with the genera l cysteine protease papain.