tert-butyl (S)-2-((1S,2S)-2-dibenzylamino-1-hydroxy-3-phenylpropyl)-pyrrolidine-1-carboxylate

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: tert-butyl (S)-2-((1S,2S)-2-dibenzylamino-1-hydroxy-3-phenylpropyl)-pyrrolidine-1-carboxylate
• 英文别名: tert-butyl (2S)-2-[(1S,2S)-2-(dibenzylamino)-1-hydroxy-3-phenylpropyl]pyrrolidine-1-carboxylate
• 化学式: C₃₂H₄₀N₂O₃
• 分子量: 500.681
• InChiKey: AXZZSWKWDQMEHZ-OIFRRMEBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.1
• 重原子数：
  37
• 可旋转键数：
  11
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  53
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  tert-butyl (S)-2-((1S,2S)-2-dibenzylamino-1-hydroxy-3-phenylpropyl)-pyrrolidine-1-carboxylate 在 10 wt% Pd(OH)2 on carbon 、 氢气 作用下， 生成 tert-butyl (S)-2-((1S,2S)-2-amino-1-hydroxy-3-phenylpropyl)pyrrolidine-1-carboxylate
  参考文献：
  名称：

  Optimization of Hydroxyethylamine Transition State Isosteres as Aspartic Protease Inhibitors by Exploiting Conformational Preferences

  摘要：

  NMR conformational analysis of a hydroxyethylamine peptide isostere developed as an aspartic protease inhibitor shows that it is a flexible architecture. Cyclization to form pyrrolidines, piperidines, or morpholines results in a preorganization of the whole system in solution. The resulting conformation is similar to the conformation of the inhibitor in the active site of BACE-1. This entropic gain results in increased affinity for the enzyme when compared with the acyclic system. For morpholines 27 and 29, the combination of steric and electronic factors is exploited to orient substituents toward S1, S1', and S2' pockets both in the solution and in the bound states. These highly preorganized molecules proved to be the most potent compounds of the series. Additionally, the morpholines, unlike the pyrrolidine and piperidine analogues, have been found to be brain penetrant BACE-1 inhibitors.

  DOI：

  10.1021/acs.jmedchem.7b01304
• 作为产物：
  描述：

  1-吡咯甲酸叔丁酯 在 10 wt% platinum on carbon 、 正丁基锂 、 氢气 作用下， 以 四氢呋喃 、 甲醇 为溶剂， -78.0 ℃ 、101.33 kPa 条件下， 反应 1.08h， 生成 tert-butyl (S)-2-((1S,2S)-2-dibenzylamino-1-hydroxy-3-phenylpropyl)-pyrrolidine-1-carboxylate
  参考文献：
  名称：

  Optimization of Hydroxyethylamine Transition State Isosteres as Aspartic Protease Inhibitors by Exploiting Conformational Preferences

  摘要：

  NMR conformational analysis of a hydroxyethylamine peptide isostere developed as an aspartic protease inhibitor shows that it is a flexible architecture. Cyclization to form pyrrolidines, piperidines, or morpholines results in a preorganization of the whole system in solution. The resulting conformation is similar to the conformation of the inhibitor in the active site of BACE-1. This entropic gain results in increased affinity for the enzyme when compared with the acyclic system. For morpholines 27 and 29, the combination of steric and electronic factors is exploited to orient substituents toward S1, S1', and S2' pockets both in the solution and in the bound states. These highly preorganized molecules proved to be the most potent compounds of the series. Additionally, the morpholines, unlike the pyrrolidine and piperidine analogues, have been found to be brain penetrant BACE-1 inhibitors.

  DOI：

  10.1021/acs.jmedchem.7b01304

文献信息

• [EN] PHENYLCARBOXAMIDE BETA-SECRETASE INHIBITORS FOR THE TREATMENT OF ALZHEIMER'S DISEASE<br/>[FR] INHIBITEURS DE BETA-SECRETASE PHENYLCARBOXAMIDE UTILISES DANS LE TRAITEMENT DE LA MALADIE D'ALZHEIMER
  申请人：MERCK & CO INC

  公开号：WO2004043916A1

  公开（公告）日：2004-05-27

  The present invention is directed to compounds which are inhibitors of the beta-secretase enzyme and that are useful in the treatment or prevention of diseases in which the beta-secretase enzyme is involved, such as Alzheimer's disease. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the beta-secretase enzyme is involved.

  本发明涉及一种抑制β-分泌酶的化合物，该化合物在治疗或预防涉及β-分泌酶的疾病方面具有用途，如阿尔茨海默病。该发明还涉及包含这些化合物的药物组合物，以及这些化合物和组合物在预防或治疗涉及β-分泌酶的疾病方面的用途。
• Optimization of Hydroxyethylamine Transition State Isosteres as Aspartic Protease Inhibitors by Exploiting Conformational Preferences
  作者：Ana B. Bueno、Javier Agejas、Howard Broughton、Robert Dally、Timothy B. Durham、Juan Félix Espinosa、Rosario González、Patric J. Hahn、Alicia Marcos、Ramón Rodríguez、Gema Sanz、José F. Soriano、David Timm、Paloma Vidal、Hsiu-Chiung Yang、James R. McCarthy

  DOI：10.1021/acs.jmedchem.7b01304

  日期：2017.12.14

  NMR conformational analysis of a hydroxyethylamine peptide isostere developed as an aspartic protease inhibitor shows that it is a flexible architecture. Cyclization to form pyrrolidines, piperidines, or morpholines results in a preorganization of the whole system in solution. The resulting conformation is similar to the conformation of the inhibitor in the active site of BACE-1. This entropic gain results in increased affinity for the enzyme when compared with the acyclic system. For morpholines 27 and 29, the combination of steric and electronic factors is exploited to orient substituents toward S1, S1', and S2' pockets both in the solution and in the bound states. These highly preorganized molecules proved to be the most potent compounds of the series. Additionally, the morpholines, unlike the pyrrolidine and piperidine analogues, have been found to be brain penetrant BACE-1 inhibitors.