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2-((2-amino-6-o-tolylquinolin-3-yl)methyl)-N-(cyclohexylmethyl) pentanamide | 1309363-93-6

中文名称
——
中文别名
——
英文名称
2-((2-amino-6-o-tolylquinolin-3-yl)methyl)-N-(cyclohexylmethyl) pentanamide
英文别名
2-[[2-amino-6-(2-methylphenyl)quinolin-3-yl]methyl]-N-(cyclohexylmethyl)pentanamide
2-((2-amino-6-o-tolylquinolin-3-yl)methyl)-N-(cyclohexylmethyl) pentanamide化学式
CAS
1309363-93-6
化学式
C29H37N3O
mdl
——
分子量
443.632
InChiKey
KSRGIPYZQZCBMH-UHFFFAOYSA-N
BEILSTEIN
——
EINECS
——
  • 物化性质
  • 计算性质
  • ADMET
  • 安全信息
  • SDS
  • 制备方法与用途
  • 上下游信息
  • 反应信息
  • 文献信息
  • 表征谱图
  • 同类化合物
  • 相关功能分类
  • 相关结构分类

计算性质

  • 辛醇/水分配系数(LogP):
    7.2
  • 重原子数:
    33
  • 可旋转键数:
    8
  • 环数:
    4.0
  • sp3杂化的碳原子比例:
    0.45
  • 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 carbonateN,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甲苯 为溶剂, 反应 6.17h, 生成 2-((2-amino-6-o-tolylquinolin-3-yl)methyl)-N-(cyclohexylmethyl) pentanamide
    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
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文献信息

  • US9296698B2
    申请人:——
    公开号:US9296698B2
    公开(公告)日:2016-03-29
  • 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).
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