(2S)-N-isobutyl-2-({[17-[methyl(methylsulfonyl)amino]-2-oxo-3-azatricyclo[13.3.1.1^6,10]icosa-1(19),6(20),7,9,15,17-hexaen-4-yl]methyl}amino)butanamide

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酰胺类
• 英文名称: (2S)-N-isobutyl-2-({[17-[methyl(methylsulfonyl)amino]-2-oxo-3-azatricyclo[13.3.1.1^6,10]icosa-1(19),6(20),7,9,15,17-hexaen-4-yl]methyl}amino)butanamide
• 英文别名: macrocyclic BACE inhibitor, 12；(2S)-2-[[17-[methyl(methylsulfonyl)amino]-2-oxo-3-azatricyclo[13.3.1.16,10]icosa-1(18),6,8,10(20),15(19),16-hexaen-4-yl]methylamino]-N-(2-methylpropyl)butanamide
• 化学式: C₃₀H₄₄N₄O₄S
• 分子量: 556.77
• InChiKey: ABGNOCQONIAVFH-RXBHZZDJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  39
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  116
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  3-碘-5-硝基苯甲酸甲酯 在 RuCl2(1,3-dimesityl-imidazolidin-2-yl)(PCy3)(=CHPh) 、 palladium on activated charcoal 、 四(三苯基膦)钯 吡啶 、 甲醇 、 sodium hydroxide 、 锂硼氢 、 乙醇 、 tin chloride 、 氢气 、 三氧化硫吡啶 、 sodium hydride 、 sodium cyanoborohydride 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 三乙胺 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 二甲基亚砜 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 82.75h， 生成 (2S)-N-isobutyl-2-({[17-[methyl(methylsulfonyl)amino]-2-oxo-3-azatricyclo[13.3.1.1^6,10]icosa-1(19),6(20),7,9,15,17-hexaen-4-yl]methyl}amino)butanamide
  参考文献：
  名称：

  β-分泌酶的大环抑制剂：在动物模型中的功能活性。

  摘要：

  通过共价交联基于间苯二甲酰胺的抑制剂的P1和P3侧链来设计β-分泌酶的大环抑制剂。与最初的铅结构相比，大环化可显着提高效能和物理性能。更重要的是，当在鼠模型中给药时，这些大环抑制剂也表现出体内淀粉样蛋白降低。

  DOI：

  10.1021/jm060884i

文献信息

• MACROCYCLIC BETA-SECRETASE INHIBITORS FOR THE TREATMENT OF ALZHEIMER'S DISEASE
  申请人：Merck Sharp & Dohme Corp.

  公开号：EP1656359B1

  公开（公告）日：2012-11-28
• Macrocyclic beta-secretase inhibitors for the treatment of alzheimer's disease
  申请人：Coburn A. Craig

  公开号：US20070037784A1

  公开（公告）日：2007-02-15

  The present invention is directed to compounds of formula I 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.
• US7329746B2
  申请人：——

  公开号：US7329746B2

  公开（公告）日：2008-02-12
• [EN] MACROCYCLIC BETA-SECRETASE INHIBITORS FOR THE TREATMENT OF ALZHEIMER'S DISEASE<br/>[FR] INHIBITEURS MACROCYCLIQUES DE LA BETA-SECRETASE DESTINES AU TRAITEMENT DE LA MALADIE D'ALZHEIMER
  申请人：MERCK & CO INC

  公开号：WO2005018545A2

  公开（公告）日：2005-03-03

  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.
• Macrocyclic Inhibitors of β-Secretase:  Functional Activity in an Animal Model
  作者：Shawn J. Stachel、Craig A. Coburn、Sethu Sankaranarayanan、Eric A. Price、Beth L. Pietrak、Qian Huang、Janet Lineberger、Amy S. Espeseth、Lixia Jin、Joan Ellis、M. Katharine Holloway、Sanjeev Munshi、Timothy Allison、Daria Hazuda、Adam J. Simon、Samuel L. Graham、Joseph P. Vacca

  DOI：10.1021/jm060884i

  日期：2006.10.1

  A macrocyclic inhibitor of beta-secretase was designed by covalently cross-linking the P1 and P3 side chains of an isophthalamide-based inhibitor. Macrocyclization resulted in significantly improved potency and physical properties when compared to the initial lead structures. More importantly, these macrocyclic inhibitors also displayed in vivo amyloid lowering when dosed in a murine model.

  通过共价交联基于间苯二甲酰胺的抑制剂的P1和P3侧链来设计β-分泌酶的大环抑制剂。与最初的铅结构相比，大环化可显着提高效能和物理性能。更重要的是，当在鼠模型中给药时，这些大环抑制剂也表现出体内淀粉样蛋白降低。