(S)-2-amino-3-(1H-imidazol-4-yl)-N-phenylpropanamide

• 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: (S)-2-amino-3-(1H-imidazol-4-yl)-N-phenylpropanamide
• 英文别名: (2S)-2-amino-3-(1H-imidazol-5-yl)-N-phenylpropanamide
• 化学式: C₁₂H₁₄N₄O
• 分子量: 230.269
• InChiKey: JKIGFJDHEPWDAK-NSHDSACASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.4
• 重原子数：
  17
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  83.8
• 氢给体数：
  3
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (S)-2-amino-3-(1H-imidazol-4-yl)-N-phenylpropanamide 在 1-羟基苯并三唑 、 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 、 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 15.0h， 生成 (2S,3S)-3-((S)-3-(1H-imidazol-4-yl)-1-oxo-1-(phenylamino)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：

  N-Boc-L-组氨酸 在 1-羟基苯并三唑 、 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 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 6.5h， 生成 (S)-2-amino-3-(1H-imidazol-4-yl)-N-phenylpropanamide
  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

• Discovery of First-in-Class Peptidomimetic Neurolysin Activators Possessing Enhanced Brain Penetration and Stability
  作者：Md. Shafikur Rahman、Shikha Kumari、Shiva Hadi Esfahani、Saeideh Nozohouri、Srinidhi Jayaraman、Nihar Kinarivala、Joanna Kocot、Andrew Baez、Delaney Farris、Thomas J. Abbruscato、Vardan T. Karamyan、Paul C. Trippier

  DOI：10.1021/acs.jmedchem.1c00759

  日期：2021.9.9

  aggravates them. Activation of Nln has therefore emerged as an intriguing target for drug discovery efforts for ischemic stroke. Herein, we report the discovery and hit-to-lead optimization of first-in-class Nln activators based on histidine-containing dipeptide hits identified from a virtual screen. Adopting a peptidomimetic approach provided lead compounds that retain the pharmacophoric histidine moiety

  肽酶溶血素 (Nln) 是一种具有切割各种神经肽的酶。中风后 Nln 的上调已确定该酶是一种关键的内源性脑保护机制，并已验证用于治疗缺血性中风的目标。Nln 在中风小鼠模型中的过度表达导致中风结果的显着改善，而药物抑制会加重它们。因此，Nln 的激活已成为缺血性中风药物发现工作的一个有趣目标。在这里，我们报告了基于从虚拟屏幕识别的含组氨酸二肽命中的一流 Nln 激活剂的发现和命中优化。采用肽模拟方法提供的先导化合物保留了药效组氨酸部分，并具有比命中支架高 40 倍以上的单位数微摩尔效力。这些化合物表现出增加 5 倍的脑穿透性、对高度同源肽酶的显着选择性、超过 65 倍的小鼠大脑稳定性增加以及在大脑中未结合的“药物样”部分。
• Unprecedented 1,1′-Carbonyldiimidazole-Mediated Amidation of ­Unprotected α-Amino Acids in Water
  作者：Rahul Jain、Rohit Sharma

  DOI：10.1055/s-2007-967965

  日期：——

  The first amidation reaction of unprotected α-amino acids in water under neutral conditions with various aliphatic, aromatic and heteroaromatic amines in the presence of coupling reagent 1,1 '-carbonyldiimidazole at ambient temperature is described.

  描述了在中性条件下，在偶联试剂 1,1'-羰基二咪唑的存在下，在中性条件下，未保护的 α-氨基酸在水中与各种脂肪族、芳香族和杂芳香族胺在环境温度下的第一次酰胺化反应。
• [EN] ENHANCERS OF NEUROLYSIN ACTIVITY<br/>[FR] AMPLIFICATEURS DE L'ACTIVITÉ DE LA NEUROLYSINE
  申请人：UNIV TEXAS TECH SYSTEM

  公开号：WO2020047185A9

  公开（公告）日：2020-09-17
• Enhancers of Neurolysin Activity
  申请人：Texas Tech University System

  公开号：US20210198647A1

  公开（公告）日：2021-07-01

  The present invention includes a composition and method of allosterically potentiating the activity of neurolysin comprising contacting the neurolysin with an amount of a histidine-containing dipeptide that is an allosteric that increases the activity of neurolysin.