(S)-2-{2-[Carboxymethyl-(3-phenyl-propyl)-amino]-acetylamino}-3-(1-trityl-1H-imidazol-4-yl)-propionic acid methyl ester | 1333227-01-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 三苯基化合物
• 英文名称: (S)-2-{2-[Carboxymethyl-(3-phenyl-propyl)-amino]-acetylamino}-3-(1-trityl-1H-imidazol-4-yl)-propionic acid methyl ester
• 英文别名: PhPr-N(EtO2H)Gly-His(1-Trt)-OMe；2-[[2-[[(2S)-1-methoxy-1-oxo-3-(1-tritylimidazol-4-yl)propan-2-yl]amino]-2-oxoethyl]-(3-phenylpropyl)amino]acetic acid
• CAS: 1333227-01-2
• 化学式: C₃₉H₄₀N₄O₅
• 分子量: 644.77
• InChiKey: GQMYQIYWRSLUQR-DHUJRADRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  48
• 可旋转键数：
  17
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  114
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (S)-2-{2-[Carboxymethyl-(3-phenyl-propyl)-amino]-acetylamino}-3-(1-trityl-1H-imidazol-4-yl)-propionic acid methyl ester 在 三异丙基硅烷 、 三氟乙酸 作用下， 反应 1.0h， 生成 (S)-2-{2-[carboxymethyl-(3-phenyl-propyl)-amino]-acetylamino}-3-(1H-imidazol-4-yl)-propionic acid methyl ester.
  参考文献：
  名称：

  Imidazole-derived 2-[N-carbamoylmethyl-alkylamino]acetic acids, substrate-dependent modulators of insulin-degrading enzyme in amyloid-β hydrolysis

  摘要：

  Insulin degrading enzyme (IDE) is a highly conserved zinc metalloprotease that is involved in the clearance of various physiologically peptides like amyloid-beta and insulin. This enzyme has been involved in the physiopathology of diabetes and Alzheimer's disease. We describe here a series of small molecules discovered by screening. Co-crystallization of the compounds with IDE revealed a binding both at the permanent exosite and at the discontinuous, conformational catalytic site. Preliminary structure activity relationships are described. Selective inhibition of amyloid-beta degradation over insulin hydrolysis was possible. Neuroblastoma cells treated with the optimized compound display a dose-dependent increase in amyloid-beta levels. (c) 2014 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2014.04.009
• 作为产物：
  描述：

  (carboxymethyl(3-phenylpropyl)amino)acetic acid 在 乙酸酐 、 N,N-二异丙基乙胺 、 三氟乙酸酐 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 4.0h， 生成 (S)-2-{2-[Carboxymethyl-(3-phenyl-propyl)-amino]-acetylamino}-3-(1-trityl-1H-imidazol-4-yl)-propionic acid methyl ester
  参考文献：
  名称：

  咪唑衍生的2- [ N-氨基甲酰基甲基-烷基氨基]乙酸与人胰岛素降解酶的双重结合剂的结构-活性关系

  摘要：

  胰岛素降解酶（IDE）是一种锌金属蛋白酶，可降解小的淀粉样肽，例如β-淀粉样蛋白和胰岛素。到目前为止，IDE特异性药理抑制剂的缺乏影响了对其在阿尔茨海默氏病生理病理学中的作用，淀粉样蛋白-α清除及其作为潜在治疗靶点的验证的了解。击中1以前是通过高通量筛选发现的。在这里，我们描述了结构活性研究，该研究需要合成48个类似物。我们发现，尽管羧酸，咪唑和叔胺对于活性至关重要，但甲酯已成功优化为酰胺或1,2,4-恶二唑。除了提高活性外，还优化了化合物在血浆和微粒体中的溶解度，亲脂性和稳定性。一些化合物在IDE的外位或催化位点上的对接或共结晶为IDE抑制提供了结构基础。在体内测定了最佳化合物44和46的药代动力学特性。结果是44（BDM43079）其甲酯前体48（BDM43124）是探索IDE作用的有用化学探针。

  DOI：

  10.1016/j.ejmech.2014.12.005

文献信息

• Ligands of insulin degrading enzyme and their uses
  申请人：Université de Lille 2 Droit et Santé

  公开号：EP2371421A1

  公开（公告）日：2011-10-05

  The invention relates to ligands of insulin degrading enzyme and to their uses. The ligands of the invention are non peptidic and bind specifically to the exosite of insulin degrading enzyme. They are useful, in particular a use in the pharmaceutical field.

  该发明涉及胰岛素降解酶的配体及其用途。该发明的配体为非肽类，并特异性结合到胰岛素降解酶的外位点。它们在药物领域中特别有用。
• [EN] LIGANDS OF INSULIN DEGRADING ENZYME AND THEIR USES<br/>[FR] LIGANDS DE L'ENZYME DÉGRADANT L'INSULINE ET LEURS UTILISATIONS
  申请人：UNIV LILLE II DROIT & SANTE

  公开号：WO2011107948A2

  公开（公告）日：2011-09-09

  The invention relates to ligands of insulin degrading enzyme and to their uses. The ligands of the invention are non peptidic and bind specifically to the exosite of insulin degrading enzyme. They are useful, in particular a use in the pharmaceutical field.
• Structure–activity relationships of imidazole-derived 2-[N-carbamoylmethyl-alkylamino]acetic acids, dual binders of human insulin-degrading enzyme
  作者：Julie Charton、Marion Gauriot、Jane Totobenazara、Nathalie Hennuyer、Julie Dumont、Damien Bosc、Xavier Marechal、Jamal Elbakali、Adrien Herledan、Xiaoan Wen、Cyril Ronco、Helene Gras-Masse、Antoine Heninot、Virginie Pottiez、Valerie Landry、Bart Staels、Wenguang G. Liang、Florence Leroux、Wei-Jen Tang、Benoit Deprez、Rebecca Deprez-Poulain

  DOI：10.1016/j.ejmech.2014.12.005

  日期：2015.1

  the structure-activity study, that required the synthesis of 48 analogues. We found that while the carboxylic acid, the imidazole and the tertiary amine were critical for activity, the methyl ester was successfully optimized to an amide or a 1,2,4-oxadiazole. Along with improving their activity, compounds were optimized for solubility, lipophilicity and stability in plasma and microsomes. The docking

  胰岛素降解酶（IDE）是一种锌金属蛋白酶，可降解小的淀粉样肽，例如β-淀粉样蛋白和胰岛素。到目前为止，IDE特异性药理抑制剂的缺乏影响了对其在阿尔茨海默氏病生理病理学中的作用，淀粉样蛋白-α清除及其作为潜在治疗靶点的验证的了解。击中1以前是通过高通量筛选发现的。在这里，我们描述了结构活性研究，该研究需要合成48个类似物。我们发现，尽管羧酸，咪唑和叔胺对于活性至关重要，但甲酯已成功优化为酰胺或1,2,4-恶二唑。除了提高活性外，还优化了化合物在血浆和微粒体中的溶解度，亲脂性和稳定性。一些化合物在IDE的外位或催化位点上的对接或共结晶为IDE抑制提供了结构基础。在体内测定了最佳化合物44和46的药代动力学特性。结果是44（BDM43079）其甲酯前体48（BDM43124）是探索IDE作用的有用化学探针。
• Imidazole-derived 2-[N-carbamoylmethyl-alkylamino]acetic acids, substrate-dependent modulators of insulin-degrading enzyme in amyloid-β hydrolysis
  作者：Julie Charton、Marion Gauriot、Qing Guo、Nathalie Hennuyer、Xavier Marechal、Julie Dumont、Malika Hamdane、Virginie Pottiez、Valerie Landry、Olivier Sperandio、Marion Flipo、Luc Buee、Bart Staels、Florence Leroux、Wei-Jen Tang、Benoit Deprez、Rebecca Deprez-Poulain

  DOI：10.1016/j.ejmech.2014.04.009

  日期：2014.5

  Insulin degrading enzyme (IDE) is a highly conserved zinc metalloprotease that is involved in the clearance of various physiologically peptides like amyloid-beta and insulin. This enzyme has been involved in the physiopathology of diabetes and Alzheimer's disease. We describe here a series of small molecules discovered by screening. Co-crystallization of the compounds with IDE revealed a binding both at the permanent exosite and at the discontinuous, conformational catalytic site. Preliminary structure activity relationships are described. Selective inhibition of amyloid-beta degradation over insulin hydrolysis was possible. Neuroblastoma cells treated with the optimized compound display a dose-dependent increase in amyloid-beta levels. (c) 2014 Elsevier Masson SAS. All rights reserved.