(3S,4S,5R)-3-(4-amino-3-propoxy-benzyl)-5-(3-tert-butyl-benzylamino)-1,1-dioxo-hexahydro-1λ6-thiopyran-4-ol hydrochloride | 1123217-42-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: (3S,4S,5R)-3-(4-amino-3-propoxy-benzyl)-5-(3-tert-butyl-benzylamino)-1,1-dioxo-hexahydro-1λ6-thiopyran-4-ol hydrochloride
• 英文别名: (3S,4S,5R)-3-(4-Amino-3-propoxy-benzyl)-5-(3-tert-butyl-benzylamino)-1,1-dioxo-hexahydro-1lambda*6*-thiopyran-4-ol hydrochloride；(3S,4S,5R)-3-[(4-amino-3-propoxyphenyl)methyl]-5-[(3-tert-butylphenyl)methylamino]-1,1-dioxothian-4-ol;hydrochloride
• CAS: 1123217-42-4
• 化学式: C₂₆H₃₈N₂O₄S*ClH
• 分子量: 511.126
• InChiKey: OJBNQWUEDOPUGG-QXMJGDHLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.88
• 重原子数：
  34
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.54
• 拓扑面积：
  110
• 氢给体数：
  4
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  (3aR,7S,7aS)-3-(3-tert-butyl-benzyl)-7-(4-nitro-3-propoxy-benzyl)-hexahydro-2H-thiopyrano[3,4-d]oxazol-2-one 5,5-dioxide 在 barium hydroxide octahydrate 、 palladium 10% on activated carbon 、 氢气 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 水 为溶剂， 反应 21.0h， 生成 (3S,4S,5R)-3-(4-amino-3-propoxy-benzyl)-5-(3-tert-butyl-benzylamino)-1,1-dioxo-hexahydro-1λ6-thiopyran-4-ol hydrochloride
  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

• AMINOBENZYL-SUBSTITUTED CYCLIC SULFONES USEFUL AS BACE INHIBITORS
  申请人：Briard Emmanuelle

  公开号：US20090054427A1

  公开（公告）日：2009-02-26

  The invention relates to novel heterocyclic compounds of the formula in which all of the variables are as defined in the specification, in free form or in salt form, to their preparation, to their use as medicaments and to medicaments comprising them.

  本发明涉及一种新型杂环化合物，其化学式为：式中所有变量均如规范中定义的自由形式或盐形式，以及它们的制备方法，用作药物的用途以及包含它们的药物。