(3aR,7S,7aS)-3-(3-tert-butyl-benzyl)-7-(3-fluoro-5-hydroxy-4-nitro-benzyl)-hexahydro-2H-thiopyrano-[3,4-d]oxazol-2-one 5,5-dioxide | 1367877-84-6

• 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: (3aR,7S,7aS)-3-(3-tert-butyl-benzyl)-7-(3-fluoro-5-hydroxy-4-nitro-benzyl)-hexahydro-2H-thiopyrano-[3,4-d]oxazol-2-one 5,5-dioxide
• CAS: 1367877-84-6
• 化学式: C₂₄H₂₇FN₂O₇S
• 分子量: 506.552
• InChiKey: IRXYYFAGEZPVQL-WVBUVRCRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.71
• 重原子数：
  35.0
• 可旋转键数：
  5.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  127.05
• 氢给体数：
  1.0
• 氢受体数：
  7.0

反应信息

• 作为反应物：
  描述：

  (3aR,7S,7aS)-3-(3-tert-butyl-benzyl)-7-(3-fluoro-5-hydroxy-4-nitro-benzyl)-hexahydro-2H-thiopyrano-[3,4-d]oxazol-2-one 5,5-dioxide 在 potassium trimethylsilonate 、 盐酸 作用下， 以 四氢呋喃 、 乙醚 、 二氯甲烷 为溶剂， 反应 1.0h， 生成 (3S,4S,5R)-3-(4-amino-3-fluoro-5-hydroxybenzyl)-5-((3-(tert-butyl)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：

  (3aR,7S,7aS)-3-(3-tert-butyl-benzyl)-7-(3,5-difluoro-4-nitro-benzyl)-hexahydro-2H-thiopyrano[3,4-d]oxazol-2-one 5,5-dioxide 在 2-羟乙基甲砜 、 sodium hydride 作用下， 以 N,N-二甲基甲酰胺 、 oil 为溶剂， 反应 1.0h， 以98%的产率得到(3aR,7S,7aS)-3-(3-tert-butyl-benzyl)-7-(3-fluoro-5-hydroxy-4-nitro-benzyl)-hexahydro-2H-thiopyrano-[3,4-d]oxazol-2-one 5,5-dioxide
  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