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

文献信息

• Design, Synthesis, and Pharmacological Evaluation of a Novel Series of Pyridopyrazine-1,6-dione γ-Secretase Modulators
  作者：Martin Pettersson、Douglas S. Johnson、Chakrapani Subramanyam、Kelly R. Bales、Christopher W. am Ende、Benjamin A. Fish、Michael E. Green、Gregory W. Kauffman、Patrick B. Mullins、Thayalan Navaratnam、Subas M. Sakya、Cory M. Stiff、Tuan P. Tran、Longfei Xie、Liming Zhang、Leslie R. Pustilnik、Beth C. Vetelino、Kathleen M. Wood、Nikolay Pozdnyakov、Patrick R. Verhoest、Christopher J. O’Donnell

  DOI：10.1021/jm401782h

  日期：2014.2.13

  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.