(3RS,5RS)-allyl 5-((tertbutoxycarbonyl)amino)-4-oxo-3-((4,4,7'-trifluoro-2'-oxospiro[cyclohexane-1,3'-indolin]-5'-yl)methyl)tetrahydro-2H-thiopyran-3-carboxylate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: (3RS,5RS)-allyl 5-((tertbutoxycarbonyl)amino)-4-oxo-3-((4,4,7'-trifluoro-2'-oxospiro[cyclohexane-1,3'-indolin]-5'-yl)methyl)tetrahydro-2H-thiopyran-3-carboxylate
• 英文别名: prop-2-enyl (3R,5R)-5-[(2-methylpropan-2-yl)oxycarbonylamino]-4-oxo-3-[(4',4',7-trifluoro-2-oxospiro[1H-indole-3,1'-cyclohexane]-5-yl)methyl]thiane-3-carboxylate
• 化学式: C₂₈H₃₃F₃N₂O₆S
• 分子量: 582.641
• InChiKey: ABLRYYSORJKNPB-UZTOHYMASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  40
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  136
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  (3RS,5RS)-allyl 5-((tertbutoxycarbonyl)amino)-4-oxo-3-((4,4,7'-trifluoro-2'-oxospiro[cyclohexane-1,3'-indolin]-5'-yl)methyl)tetrahydro-2H-thiopyran-3-carboxylate 在 吗啉 、 盐酸 、 lithium aluminium tetrahydride 、 四(三苯基膦)钯 、 potassium peroxymonosulfate 、 sodium acetate 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 水 为溶剂， 反应 15.25h， 生成 (3RS₄SR,5SR)-3-((3-(tertbutyl)benzyl)amino)-5-((4,4,7'-trifluoro-2'-oxospiro[cyclohexane-1,3'-indolin]-5'-yl)methyl)-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
• 作为产物：
  描述：

  (R)-4-tert-butoxycarbonylamino-3-oxo-5-tritylsulfanyl-pentanoic acid allyl ester 在 哌啶 、 偶氮二甲酸二异丙酯 、 溶剂黄146 、 三苯基膦 作用下， 以 四氢呋喃 为溶剂， 反应 0.5h， 生成 (3RS,5RS)-allyl 5-((tertbutoxycarbonyl)amino)-4-oxo-3-((4,4,7'-trifluoro-2'-oxospiro[cyclohexane-1,3'-indolin]-5'-yl)methyl)tetrahydro-2H-thiopyran-3-carboxylate
  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