3-(2-(4-methoxybenzylamino)-6-bromoquinolin-3-yl)-2-methylacrylic acid | 1321992-09-9

• 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: 3-(2-(4-methoxybenzylamino)-6-bromoquinolin-3-yl)-2-methylacrylic acid
• 英文别名: 3-[6-Bromo-2-[(4-methoxyphenyl)methylamino]quinolin-3-yl]-2-methylprop-2-enoic acid
• CAS: 1321992-09-9
• 化学式: C₂₁H₁₉BrN₂O₃
• 分子量: 427.297
• InChiKey: PKRWNDKUQMIGTE-UHFFFAOYSA-N

物化性质

• 沸点：
  594.0±50.0 °C(predicted)
• 密度：
  1.478±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  27
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  71.4
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  3-(2-(4-methoxybenzylamino)-6-bromoquinolin-3-yl)-2-methylacrylic acid 在 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 二氯双[二叔丁基-(4-二甲基氨基苯基)膦]钯(II) 、 5%-palladium/activated carbon 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetra fluoroborate 、 氢气 、 potassium acetate 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 1,3-二噁烷 、 N-甲基吡咯烷酮 、 乙醇 、 水 为溶剂， 反应 35.0h， 生成 3-(6-(2-acetylphenyl)-2-aminoquinolin-3-yl)-N-(3,3-dimethylbutyl)-2-methylpropanamide
  参考文献：
  名称：

  From Fragment Screening to In Vivo Efficacy: Optimization of a Series of 2-Aminoquinolines as Potent Inhibitors of Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1)

  摘要：

  Using fragment-based screening of a focused fragment library, 2-aminoquinoline I was identified as an initial hit for BACE1. Further SAR development was supported by X-ray structures of BACE1 cocrystallized with various ligands and molecular modeling studies to expedite the discovery of potent compounds. These strategies enabled us to integrate the C-3 side chain on 2-aminoquinoline 1 extending deep into the P2' binding pocket of BACE1 and enhancing the ligand's potency. We were able to improve the BACE1 potency to subnanomolar range, over 10(6)-fold more potent than the initial hit (900 mu M). Further elaboration of the physical properties of the lead compounds to those more consistent with good blood-brain barrier permeability led to inhibitors with greatly improved cellular activity and permeability. Compound 59 showed an IC50 value of 11 nM on BACE1 and cellular activity of 80 nM, This compound was advanced into rat pharmacokinetic and pharmacodynamic studies and demonstrated significant reduction of A beta levels in cerebrospinal fluid (CSF).

  DOI：

  10.1021/jm200544q
• 作为产物：
  描述：

  6-溴-2-((4-甲氧基苄基)氨基)喹啉-3-甲醛 在 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 lithium chloride 、 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 乙腈 为溶剂， 反应 13.0h， 生成 3-(2-(4-methoxybenzylamino)-6-bromoquinolin-3-yl)-2-methylacrylic acid
  参考文献：
  名称：

  From Fragment Screening to In Vivo Efficacy: Optimization of a Series of 2-Aminoquinolines as Potent Inhibitors of Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1)

  摘要：

  Using fragment-based screening of a focused fragment library, 2-aminoquinoline I was identified as an initial hit for BACE1. Further SAR development was supported by X-ray structures of BACE1 cocrystallized with various ligands and molecular modeling studies to expedite the discovery of potent compounds. These strategies enabled us to integrate the C-3 side chain on 2-aminoquinoline 1 extending deep into the P2' binding pocket of BACE1 and enhancing the ligand's potency. We were able to improve the BACE1 potency to subnanomolar range, over 10(6)-fold more potent than the initial hit (900 mu M). Further elaboration of the physical properties of the lead compounds to those more consistent with good blood-brain barrier permeability led to inhibitors with greatly improved cellular activity and permeability. Compound 59 showed an IC50 value of 11 nM on BACE1 and cellular activity of 80 nM, This compound was advanced into rat pharmacokinetic and pharmacodynamic studies and demonstrated significant reduction of A beta levels in cerebrospinal fluid (CSF).

  DOI：

  10.1021/jm200544q