2-(benzyl{[(1S,2S)-2-methylcyclopropyl]methyl}amino)-6-[methyl(methylsulfonyl)amino]isonicotinic acid | 935470-37-4

• 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: 2-(benzyl{[(1S,2S)-2-methylcyclopropyl]methyl}amino)-6-[methyl(methylsulfonyl)amino]isonicotinic acid
• CAS: 935470-37-4
• 化学式: C₂₀H₂₅N₃O₄S
• 分子量: 403.502
• InChiKey: UPKVSOISFVTTRO-WMLDXEAASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.84
• 重原子数：
  28.0
• 可旋转键数：
  8.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  90.81
• 氢给体数：
  1.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  2-(benzyl{[(1S,2S)-2-methylcyclopropyl]methyl}amino)-6-[methyl(methylsulfonyl)amino]isonicotinic acid 在 palladium dihydroxide N-羟基-7-氮杂苯并三氮唑 、 氢气 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 乙醇 为溶剂， 生成 N-[(2S)-1-(3,5-difluorophenyl)-3-hydroxypropan-2-yl]-2-({[(1S,2S)-2-methylcyclopropyl]methyl}amino)-6-(N-methylmethanesulfonamido)pyridine-4-carboxamide
  参考文献：
  名称：

  Discovery and SAR of isonicotinamide BACE-1 inhibitors that bind β-secretase in a N-terminal 10s-loop down conformation

  摘要：

  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.

  DOI：

  10.1016/j.bmcl.2006.12.051
• 作为产物：
  描述：

  methyl 2-chloro-6-[methyl(methylsulfonyl)amino]isonicotinate 在 二(三叔丁基膦)钯 sodium hydroxide 、 potassium phosphate 作用下， 以 四氢呋喃 、 甲醇 、 N,N-二甲基乙酰胺 为溶剂， 生成 2-(benzyl{[(1S,2S)-2-methylcyclopropyl]methyl}amino)-6-[methyl(methylsulfonyl)amino]isonicotinic acid
  参考文献：
  名称：

  Discovery and SAR of isonicotinamide BACE-1 inhibitors that bind β-secretase in a N-terminal 10s-loop down conformation

  摘要：

  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.

  DOI：

  10.1016/j.bmcl.2006.12.051

文献信息

• Discovery of Isonicotinamide Derived β-Secretase Inhibitors:  In Vivo Reduction of β-Amyloid
  作者：Matthew G. Stanton、Shaun R. Stauffer、Alison R. Gregro、Melissa Steinbeiser、Philippe Nantermet、Sethu Sankaranarayanan、Eric A. Price、Guoxin Wu、Ming-Chih Crouthamel、Joan Ellis、Ming-Tain Lai、Amy S. Espeseth、Xiao-Ping Shi、Lixia Jin、Dennis Colussi、Beth Pietrak、Qian Huang、Min Xu、Adam J. Simon、Samuel L. Graham、Joseph P. Vacca、Harold Selnick

  DOI：10.1021/jm070272d

  日期：2007.7.1

  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.