N-[(1S,2R)-2-azido-1-benzyl-3-methoxypropyl]-2-(methyl{[(1S,2S)-2-methylcyclopropyl]methyl}amino)-6-[methyl(methylsulfonyl)amino]isonicotinamide | 946420-62-8

• 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: N-[(1S,2R)-2-azido-1-benzyl-3-methoxypropyl]-2-(methyl{[(1S,2S)-2-methylcyclopropyl]methyl}amino)-6-[methyl(methylsulfonyl)amino]isonicotinamide
• CAS: 946420-62-8
• 化学式: C₂₅H₃₅N₇O₄S
• 分子量: 529.663
• InChiKey: VHVVRDDICIDDNC-XGARDCMYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.24
• 重原子数：
  37.0
• 可旋转键数：
  13.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  140.6
• 氢给体数：
  1.0
• 氢受体数：
  7.0

反应信息

• 作为反应物：
  描述：

  N-[(1S,2R)-2-azido-1-benzyl-3-methoxypropyl]-2-(methyl{[(1S,2S)-2-methylcyclopropyl]methyl}amino)-6-[methyl(methylsulfonyl)amino]isonicotinamide 在 palladium on activated charcoal 氢气 作用下， 以 甲醇 为溶剂， 反应 2.0h， 以38%的产率得到N-[(1S,2R)-2-amino-1-benzyl-3-methoxypropyl]-2-(methyl{[(1S,2S)-2-methylcyclopropyl]methyl}amino)-6-[methyl(methylsulfonyl)amino]isonicotinamide monohydrochloride
  参考文献：
  名称：

  Discovery of Isonicotinamide Derived β-Secretase Inhibitors:  In Vivo Reduction of β-Amyloid

  摘要：

  beta-Secretase inhibition offers an exciting opportunity for therapeutic intervention in the progression of Alzheimer's disease. A series of isonicotinamides derived from traditional aspartyl protease transition state isostere inhibitors has been optimized to yield low nanomolar inhibitors with sufficient penetration across the blood-brain barrier to demonstrate beta-amyloid lowering in a murine model.

  DOI：

  10.1021/jm070272d
• 作为产物：
  描述：

  N-benzyl[(1S,2S)-2-methylcyclopropyl]methanamine 在 palladium dihydroxide 、 bis(tri-tert-butylphosphine)palladium(0) potassium phosphate 、 N-羟基-7-氮杂苯并三氮唑 、 氢气 、 三乙酰氧基硼氢化钠 、 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 作用下， 以 甲醇 、 乙醇 、 二氯甲烷 、 N,N-二甲基乙酰胺 、 水 为溶剂， 20.0~130.0 ℃ 、101.33 kPa 条件下， 反应 20.0h， 生成 N-[(1S,2R)-2-azido-1-benzyl-3-methoxypropyl]-2-(methyl{[(1S,2S)-2-methylcyclopropyl]methyl}amino)-6-[methyl(methylsulfonyl)amino]isonicotinamide
  参考文献：
  名称：

  Discovery of Isonicotinamide Derived β-Secretase Inhibitors:  In Vivo Reduction of β-Amyloid

  摘要：

  beta-Secretase inhibition offers an exciting opportunity for therapeutic intervention in the progression of Alzheimer's disease. A series of isonicotinamides derived from traditional aspartyl protease transition state isostere inhibitors has been optimized to yield low nanomolar inhibitors with sufficient penetration across the blood-brain barrier to demonstrate beta-amyloid lowering in a murine model.

  DOI：

  10.1021/jm070272d

文献信息

• Discovery and SAR of isonicotinamide BACE-1 inhibitors that bind β-secretase in a N-terminal 10s-loop down conformation
  作者：Shaun R. Stauffer、Matthew G. Stanton、Alison R. Gregro、Melissa A. Steinbeiser、Jennifer R. Shaffer、Philippe G. Nantermet、James C. Barrow、Kenneth E. Rittle、Dennis Collusi、Amy S. Espeseth、Ming-Tain Lai、Beth L. Pietrak、M. Katharine Holloway、Georgia B. McGaughey、Sanjeev K. Munshi、Jerome H. Hochman、Adam J. Simon、Harold G. Selnick、Samuel L. Graham、Joseph P. Vacca

  DOI：10.1016/j.bmcl.2006.12.051

  日期：2007.3

  A series of low-molecular weight 2,6-diamino-isonicotinamide BACE-I inhibitors containing an amine transition-state isostere were synthesized and shown to be highly potent in both enzymatic and cell-based assays. These inhibitors contain a trans-S,S-methyl cyclopropane P-3 which bind BACE-1 in a 10s-loop down conformation giving rise to highly potent compounds with favorable molecular weight and moderate to high susceptibility to P-glycoprotein (P-gp) efflux. (c) 2007 Elsevier Ltd. All rights reserved.