5-hydroxy-6-(4-methyl-1H-imidazol-1-yl)-2-[3-(trifluoromethyl)-benzyl]isoquinolin-1(2H)-one | 1548942-32-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异喹啉及其衍生物
• 英文名称: 5-hydroxy-6-(4-methyl-1H-imidazol-1-yl)-2-[3-(trifluoromethyl)-benzyl]isoquinolin-1(2H)-one
• 英文别名: 5-Hydroxy-6-(4-methylimidazol-1-yl)-2-[[3-(trifluoromethyl)phenyl]methyl]isoquinolin-1-one；5-hydroxy-6-(4-methylimidazol-1-yl)-2-[[3-(trifluoromethyl)phenyl]methyl]isoquinolin-1-one
• CAS: 1548942-32-0
• 化学式: C₂₁H₁₆F₃N₃O₂
• 分子量: 399.372
• InChiKey: BAFZDGGODDOWMV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  29
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  58.4
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  5-hydroxy-6-(4-methyl-1H-imidazol-1-yl)-2-[3-(trifluoromethyl)-benzyl]isoquinolin-1(2H)-one 在 palladium 10% on activated carbon 、 氢气 作用下， 以 甲醇 为溶剂， 60.0 ℃ 、5.0 MPa 条件下， 以97%的产率得到5-hydroxy-6-(4-methyl-1H-imidazol-1-yl)-2-[3-(trifluoromethyl)-benzyl]-3,4-dihydroisoquinolin-1(2H)-one
  参考文献：
  名称：

  Design, Synthesis, and Pharmacological Evaluation of a Novel Series of Pyridopyrazine-1,6-dione γ-Secretase Modulators

  摘要：

  Herein we describe the design and synthesis of a novel series of gamma-secretase modulators (GSMs) that incorporates a pyridopiperazine-1,6-dione ring system. To align improved potency with favorable ADME and in vitro safety, we applied prospective physicochemical property-driven design coupled with parallel medicinal chemistry techniques to arrive at a novel series containing a conformationally restricted core. Lead compound 51 exhibited good in vitro potency and ADME, which translated into a favorable in vivo pharmacokinetic profile. Furthermore, robust reduction of brain A beta 42 was observed in guinea pig at 30 mg/kg dosed orally. Through chemical biology efforts involving the design and synthesis of a clickable photoreactive probe, we demonstrated specific labeling of the presenilin N-terminal fragment (PS1-NTF) within the gamma-secretase complex, thus gaining insight into the binding site of this series of GSMs.

  DOI：

  10.1021/jm401782h
• 作为产物：
  描述：

  3-氟-2-甲氧基苯甲醛 在 哌啶 、 氯化亚砜 、 sodium azide 、 sodium hydride 、 potassium carbonate 作用下， 以 吡啶 、 水 、 N,N-二甲基甲酰胺 、 邻二氯苯 、 丙酮 、 mineral oil 为溶剂， 反应 208.0h， 生成 5-hydroxy-6-(4-methyl-1H-imidazol-1-yl)-2-[3-(trifluoromethyl)-benzyl]isoquinolin-1(2H)-one
  参考文献：
  名称：

  Design, Synthesis, and Pharmacological Evaluation of a Novel Series of Pyridopyrazine-1,6-dione γ-Secretase Modulators

  摘要：

  Herein we describe the design and synthesis of a novel series of gamma-secretase modulators (GSMs) that incorporates a pyridopiperazine-1,6-dione ring system. To align improved potency with favorable ADME and in vitro safety, we applied prospective physicochemical property-driven design coupled with parallel medicinal chemistry techniques to arrive at a novel series containing a conformationally restricted core. Lead compound 51 exhibited good in vitro potency and ADME, which translated into a favorable in vivo pharmacokinetic profile. Furthermore, robust reduction of brain A beta 42 was observed in guinea pig at 30 mg/kg dosed orally. Through chemical biology efforts involving the design and synthesis of a clickable photoreactive probe, we demonstrated specific labeling of the presenilin N-terminal fragment (PS1-NTF) within the gamma-secretase complex, thus gaining insight into the binding site of this series of GSMs.

  DOI：

  10.1021/jm401782h