(E)-N'-(4-(((3aR,7S,7aS)-3-(3-tert-butylbenzyl)-5,5-dioxido-2-oxohexahydro-2H-thiopyrano[3,4-d]oxazol-7-yl)-methyl-2-fluoro-6-iodophenyl))-N,N-dimethylformimidamide | 1367877-58-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 英文名称: (E)-N'-(4-(((3aR,7S,7aS)-3-(3-tert-butylbenzyl)-5,5-dioxido-2-oxohexahydro-2H-thiopyrano[3,4-d]oxazol-7-yl)-methyl-2-fluoro-6-iodophenyl))-N,N-dimethylformimidamide
• CAS: 1367877-58-4
• 化学式: C₂₇H₃₃FIN₃O₄S
• 分子量: 641.546
• InChiKey: VVFHUBMCZKEDOB-OQSFVBKFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.93
• 重原子数：
  37.0
• 可旋转键数：
  6.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  79.28
• 氢给体数：
  0.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  (E)-N'-(4-(((3aR,7S,7aS)-3-(3-tert-butylbenzyl)-5,5-dioxido-2-oxohexahydro-2H-thiopyrano[3,4-d]oxazol-7-yl)-methyl-2-fluoro-6-iodophenyl))-N,N-dimethylformimidamide 在 copper(l) iodide 、 potassium trimethylsilonate 、 zinc(II) chloride 作用下， 以 四氢呋喃 、 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 18.5h， 生成 (3S,4S,5R)-3-(4-amino-3-fluoro-5-((S)-3,3,3-trifluoro-2-methoxypropyl)benzyl)-5-((3-(tertbutyl)benzyl)amino)-4-hydroxytetrahydro-2H-thiopyran 1,1-dioxide dihydrochloride
  参考文献：
  名称：

  Discovery of Cyclic Sulfone Hydroxyethylamines as Potent and Selective β-Site APP-Cleaving Enzyme 1 (BACE1) Inhibitors: Structure-Based Design and in Vivo Reduction of Amyloid β-Peptides

  摘要：

  Structure-based design of a series of cyclic hydroxyethylamine BACE1 inhibitors allowed the rational incorporation of prime- and nonprime-side fragments to a central core template without any amide functionality. The core scaffold selection and the structure activity relationship development were supported by molecular modeling studies and by X-ray analysis of BACE1 complexes with various ligands to expedite the optimization of the series. The direct extension from P1-aryl- and heteroaryl moieties into the S3 binding pocket allowed the enhancement of potency and selectivity over cathepsin D. Restraining the design and synthesis of compounds to a physicochemical property space consistent with central nervous system drugs led to inhibitors with improved blood brain barrier permeability. Guided by structure-based optimization, we were able to obtain highly potent compounds such as 60p with enzymatic and cellular IC50 values of 2 and 50 nM, respectively, and with >200-fold selectivity over cathepsin D. Pharmacodynamic studies in APPS1/16 transgenic mice at oral doses of 180 mu mol/kg demonstrated significant reduction of brain A beta levels.

  DOI：

  10.1021/jm300069y
• 作为产物：
  描述：

  3-氟-4-硝基溴化苄 在 吗啉 、 盐酸 、 4-二甲氨基吡啶 、 lithium aluminium tetrahydride 、 四(三苯基膦)钯 、 potassium peroxymonosulfate 、 palladium 10% on activated carbon 、 氢气 、 sodium acetate 、 potassium carbonate 、 N,N,N-trimethylbenzenemethanaminium dichloroiodate 、 N,N-二异丙基乙胺 、 calcium carbonate 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 乙醇 、 正己烷 、 二氯甲烷 、 氯仿 、 水 、 异丙醇 、 丙酮 、 甲苯 、 乙腈 为溶剂， 反应 85.75h， 生成 (E)-N'-(4-(((3aR,7S,7aS)-3-(3-tert-butylbenzyl)-5,5-dioxido-2-oxohexahydro-2H-thiopyrano[3,4-d]oxazol-7-yl)-methyl-2-fluoro-6-iodophenyl))-N,N-dimethylformimidamide
  参考文献：
  名称：

  Discovery of Cyclic Sulfone Hydroxyethylamines as Potent and Selective β-Site APP-Cleaving Enzyme 1 (BACE1) Inhibitors: Structure-Based Design and in Vivo Reduction of Amyloid β-Peptides

  摘要：

  Structure-based design of a series of cyclic hydroxyethylamine BACE1 inhibitors allowed the rational incorporation of prime- and nonprime-side fragments to a central core template without any amide functionality. The core scaffold selection and the structure activity relationship development were supported by molecular modeling studies and by X-ray analysis of BACE1 complexes with various ligands to expedite the optimization of the series. The direct extension from P1-aryl- and heteroaryl moieties into the S3 binding pocket allowed the enhancement of potency and selectivity over cathepsin D. Restraining the design and synthesis of compounds to a physicochemical property space consistent with central nervous system drugs led to inhibitors with improved blood brain barrier permeability. Guided by structure-based optimization, we were able to obtain highly potent compounds such as 60p with enzymatic and cellular IC50 values of 2 and 50 nM, respectively, and with >200-fold selectivity over cathepsin D. Pharmacodynamic studies in APPS1/16 transgenic mice at oral doses of 180 mu mol/kg demonstrated significant reduction of brain A beta levels.

  DOI：

  10.1021/jm300069y