(R)-3-(2-amino-6-o-tolylquinolin-3-yl)-N-benzyl-2-methylpropanamide | 1321991-99-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: (R)-3-(2-amino-6-o-tolylquinolin-3-yl)-N-benzyl-2-methylpropanamide
• 英文别名: (2R)-3-[2-amino-6-(2-methylphenyl)quinolin-3-yl]-N-benzyl-2-methylpropanamide
• CAS: 1321991-99-4
• 化学式: C₂₇H₂₇N₃O
• 分子量: 409.531
• InChiKey: USPPVRYTYZVYSL-LJQANCHMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  31
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  68
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  6-溴喹啉-3-羧酸甲酯 在 manganese(IV) oxide 、 四(三苯基膦)钯 、 氯化亚砜 、 lithium hydroxide monohydrate 、 palladium 10% on activated carbon 、 4-甲苯磺酸酐 、 氢气 、 二异丁基氢化铝 、 potassium carbonate 、 N,N-二异丙基乙胺 、 间氯过氧苯甲酸 、 三氟乙酸 作用下， 以 甲醇 、 dichlorormethane 、 乙醇 、 正己烷 、 二氯甲烷 、 氯仿 、 三氟甲苯 、 水 、 甲苯 为溶剂， 反应 9.17h， 生成 (S)-3-(2-amino-6-o-tolylquinolin-3-yl)-N-benzyl-2-methylpropanamide 、 (R)-3-(2-amino-6-o-tolylquinolin-3-yl)-N-benzyl-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

文献信息

• 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)
  作者：Yuan Cheng、Ted C. Judd、Michael D. Bartberger、James Brown、Kui Chen、Robert T. Fremeau、Dean Hickman、Stephen A. Hitchcock、Brad Jordan、Vivian Li、Patricia Lopez、Steven W. Louie、Yi Luo、Klaus Michelsen、Thomas Nixey、Timothy S. Powers、Claire Rattan、E. Allen Sickmier、David J. St. Jean、Robert C. Wahl、Paul H. Wen、Stephen Wood

  DOI：10.1021/jm200544q

  日期：2011.8.25

  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).