(3S,4S,5R)-3-(4-amino-3-bromo-5-fluorobenzyl)-5-((3-(1,1-difluoroethyl)benzyl)amino)-4-hydroxytetrahydro-2H-thiopyran 1,1-dioxide | 1123171-35-6

• 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: (3S,4S,5R)-3-(4-amino-3-bromo-5-fluorobenzyl)-5-((3-(1,1-difluoroethyl)benzyl)amino)-4-hydroxytetrahydro-2H-thiopyran 1,1-dioxide
• 英文别名: (3S,4S,5R)-3-(4-amino-3-bromo-5-fluoro-benzyl)-5-[3-(1,1-difluoro-ethyl)-benzylamino]-1,1-dioxo-hexahydro-1λ6-thiopyran-4-ol；(3s,4s,5r)-3-(4-Amino-3-Bromo-5-Fluorobenzyl)-5-{[3-(1,1-Difluoroethyl)benzyl]amino}tetrahydro-2h-Thiopyran-4-Ol 1,1-Dioxide；(3S,4S,5R)-3-[(4-amino-3-bromo-5-fluorophenyl)methyl]-5-[[3-(1,1-difluoroethyl)phenyl]methylamino]-1,1-dioxothian-4-ol
• CAS: 1123171-35-6
• 化学式: C₂₁H₂₄BrF₃N₂O₃S
• 分子量: 521.398
• InChiKey: QBRKIXCNLLQOPH-WNYOCNMUSA-N

物化性质

• 沸点：
  650.7±55.0 °C(predicted)
• 密度：
  1.55±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  31
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  101
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  3-氟-4-硝基溴化苄 在 吗啉 、 盐酸 、 lithium aluminium tetrahydride 、 四(三苯基膦)钯 、 potassium peroxymonosulfate 、 1,3-di-n-butyl-1H-imidazol-3-ium tribromide 、 sodium acetate 、 potassium 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 、 水 、 异丙醇 、 丙酮 为溶剂， 反应 38.25h， 生成 (3S,4S,5R)-3-(4-amino-3-bromo-5-fluorobenzyl)-5-((3-(1,1-difluoroethyl)benzyl)amino)-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

文献信息

• 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
  作者：Heinrich Rueeger、Rainer Lueoend、Olivier Rogel、Jean-Michel Rondeau、Henrik Möbitz、Rainer Machauer、Laura Jacobson、Matthias Staufenbiel、Sandrine Desrayaud、Ulf Neumann

  DOI：10.1021/jm300069y

  日期：2012.4.12

  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.