5-(bromomethyl)-3-(2,2-difluoroethyl)-1-tosyl-1H-indole | 1367877-15-3

• 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: 5-(bromomethyl)-3-(2,2-difluoroethyl)-1-tosyl-1H-indole
• 英文别名: 5-(Bromomethyl)-3-(2,2-difluoroethyl)-1-(4-methylphenyl)sulfonylindole
• CAS: 1367877-15-3
• 化学式: C₁₈H₁₆BrF₂NO₂S
• 分子量: 428.297
• InChiKey: LPAKUHPCNAPNMW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.3
• 重原子数：
  25
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  47.4
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  5-(bromomethyl)-3-(2,2-difluoroethyl)-1-tosyl-1H-indole 在 吗啉 、 盐酸 、 甲醇 、 四(三苯基膦)钯 、 potassium peroxymonosulfate 、 BH₄^(1-)*C₄H₈O*Ca⁽²⁺⁾ 、 sodium acetate 、 potassium carbonate 、 sodium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 水 、 丙酮 为溶剂， 反应 43.25h， 生成 (3RS,4SR,5SR)-3-(3-tert-butyl-benzylamino)-5-[3-(2,2-difluoro-ethyl)-1H-indol-5-ylmethyl]-1,1-dioxo-tetrahydro-2H-thiopyran-4-ol
  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：

  N-tosyl-5-bromoindole 在 aluminum (III) chloride 、 bis-triphenylphosphine-palladium(II) chloride 、 sodium tetrahydroborate 、 四氧化锇 、 硼烷四氢呋喃络合物 、 三溴化磷 、 sodium hydride 、 caesium carbonate 、 N-甲基吗啉氧化物 作用下， 以 四氢呋喃 、 甲醇 、 乙醚 、 乙醇 、 二氯甲烷 、 methnaol 、 N,N-二甲基甲酰胺 、 oil 为溶剂， 反应 92.0h， 生成 5-(bromomethyl)-3-(2,2-difluoroethyl)-1-tosyl-1H-indole
  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.