(3R,4S,5S)-3-((3-(tert-butyl)benzyl)amino)-5-(3-fluoro-5-(2-methoxyethoxy)-4-nitrobenzyl)-4-hydroxytetrahydro-2H-thiopyran 1,1-dioxide | 1204343-85-0

• 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: (3R,4S,5S)-3-((3-(tert-butyl)benzyl)amino)-5-(3-fluoro-5-(2-methoxyethoxy)-4-nitrobenzyl)-4-hydroxytetrahydro-2H-thiopyran 1,1-dioxide
• CAS: 1204343-85-0
• 化学式: C₂₆H₃₅FN₂O₇S
• 分子量: 538.638
• InChiKey: QLTCFGRFRGIKSU-WPWBMXPQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.16
• 重原子数：
  37.0
• 可旋转键数：
  10.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.54
• 拓扑面积：
  128.0
• 氢给体数：
  2.0
• 氢受体数：
  8.0

反应信息

• 作为反应物：
  描述：

  (3R,4S,5S)-3-((3-(tert-butyl)benzyl)amino)-5-(3-fluoro-5-(2-methoxyethoxy)-4-nitrobenzyl)-4-hydroxytetrahydro-2H-thiopyran 1,1-dioxide 在 sodium tetrahydroborate 、 nickel(II) chloride hexahydrate 作用下， 以 甲醇 为溶剂， 反应 2.0h， 生成 (3S,4S,5R)-3-(4-amino-3-fluoro-5-(2-methoxyethoxy)benzyl)-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：

  3,5-二氟-4-硝基苯腈 在 盐酸 、 lithium aluminium tetrahydride 、 氯化亚砜 、 potassium peroxymonosulfate 、 sodium acetate 、 palladium diacetate 、 三溴化磷 、 二异丁基氢化铝 、 potassium carbonate 、 三乙胺 、 三苯基膦 、 potassium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 乙醇 、 正己烷 、 正庚烷 、 二氯甲烷 、 甲基叔丁基醚 、 水 、 丙酮 为溶剂， 反应 56.08h， 生成 (3R,4S,5S)-3-((3-(tert-butyl)benzyl)amino)-5-(3-fluoro-5-(2-methoxyethoxy)-4-nitrobenzyl)-4-hydroxytetrahydro-2H-thiopyran 1,1-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