1-(4-Benzyloxy-phenyl)-2-(3-fluoro-phenyl)-6-methoxy-1-methyl-1,2,3,4-tetrahydro-isoquinoline | 645393-09-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 四氢异喹啉
• 英文名称: 1-(4-Benzyloxy-phenyl)-2-(3-fluoro-phenyl)-6-methoxy-1-methyl-1,2,3,4-tetrahydro-isoquinoline
• 英文别名: 2-(3-Fluorophenyl)-6-methoxy-1-methyl-1-(4-phenylmethoxyphenyl)-3,4-dihydroisoquinoline
• CAS: 645393-09-5
• 化学式: C₃₀H₂₈FNO₂
• 分子量: 453.556
• InChiKey: GMEBIGOJQHXFFV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7
• 重原子数：
  34
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  21.7
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  1-(4-Benzyloxy-phenyl)-2-(3-fluoro-phenyl)-6-methoxy-1-methyl-1,2,3,4-tetrahydro-isoquinoline 在 三氯化铝 、 sodium hydride 、 N,N-二甲基苯胺 作用下， 以 1,4-二氧六环 、 二氯甲烷 为溶剂， 生成 2-(3-Fluoro-phenyl)-6-methoxy-1-methyl-1-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1,2,3,4-tetrahydro-isoquinoline
  参考文献：
  名称：

  Estrogen Receptor Modulators:  Identification and Structure−Activity Relationships of Potent ERα-Selective Tetrahydroisoquinoline Ligands

  摘要：

  As part of a program aimed at the development of selective estrogen receptor modulators (SERMs), tetrahydroisoquinoline derivative 27 was discovered by high throughput screening. Successive replacements of the p-F substituent of 27 by an aminoethoxy side chain and of the 1-H of the tetrahydroisoquinoline core by a 1-Me group provided analogues 19 and 20. These compounds showed potencies in a cell-based reporter gene assay (ERE assay) varying between 0.6 and 20 nM and displayed antagonist behaviors in the MCF-7 human breast adenocarcinoma cell line with IC(50)s in the range of 2-36 nM. The effect of N-phenyl substituents on the activity and pharmacokinetic properties of tetrahydroisoquinoline analogues was explored. As a result of this investigation, two potent derivatives bearing a p-F N-aryl group, 19c and 20c, were discovered as candidates suitable for further profiling. To gain insight into the ligand-receptor interaction, the X-ray crystallographic structure of the 1-H tetrahydroisoquinoline derivative (R)-18a in complex with ERalpha-ligand binding domain (LBD)(301-553)/C-->S triple mutant was solved to 2.28 Angstrom. An overlay of this X-ray crystal structure with that reported for the complex of ERalpha-LBD301-553/carboxymethylated C and raloxifene (5) shows that both compounds bind to the same cleft of the receptor and display comparable binding modes, with differences being observed in the conformation of their "D-ring" phenyl groups.

  DOI：

  10.1021/jm030086h
• 作为产物：
  描述：

  间氟碘苯 在 copper(l) iodide 、 potassium carbonate 作用下， 以 四氢呋喃 、 乙醚 、 正己烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 0.17h， 生成 1-(4-Benzyloxy-phenyl)-2-(3-fluoro-phenyl)-6-methoxy-1-methyl-1,2,3,4-tetrahydro-isoquinoline
  参考文献：
  名称：

  Estrogen Receptor Modulators:  Identification and Structure−Activity Relationships of Potent ERα-Selective Tetrahydroisoquinoline Ligands

  摘要：

  As part of a program aimed at the development of selective estrogen receptor modulators (SERMs), tetrahydroisoquinoline derivative 27 was discovered by high throughput screening. Successive replacements of the p-F substituent of 27 by an aminoethoxy side chain and of the 1-H of the tetrahydroisoquinoline core by a 1-Me group provided analogues 19 and 20. These compounds showed potencies in a cell-based reporter gene assay (ERE assay) varying between 0.6 and 20 nM and displayed antagonist behaviors in the MCF-7 human breast adenocarcinoma cell line with IC(50)s in the range of 2-36 nM. The effect of N-phenyl substituents on the activity and pharmacokinetic properties of tetrahydroisoquinoline analogues was explored. As a result of this investigation, two potent derivatives bearing a p-F N-aryl group, 19c and 20c, were discovered as candidates suitable for further profiling. To gain insight into the ligand-receptor interaction, the X-ray crystallographic structure of the 1-H tetrahydroisoquinoline derivative (R)-18a in complex with ERalpha-ligand binding domain (LBD)(301-553)/C-->S triple mutant was solved to 2.28 Angstrom. An overlay of this X-ray crystal structure with that reported for the complex of ERalpha-LBD301-553/carboxymethylated C and raloxifene (5) shows that both compounds bind to the same cleft of the receptor and display comparable binding modes, with differences being observed in the conformation of their "D-ring" phenyl groups.

  DOI：

  10.1021/jm030086h

文献信息

• Estrogen Receptor Modulators:  Identification and Structure−Activity Relationships of Potent ERα-Selective Tetrahydroisoquinoline Ligands
  作者：Johanne Renaud、Serge François Bischoff、Thomas Buhl、Philipp Floersheim、Brigitte Fournier、Christine Halleux、Joerg Kallen、Hansjoerg Keller、Jean-Marc Schlaeppi、Wilhelm Stark

  DOI：10.1021/jm030086h

  日期：2003.7.1

  As part of a program aimed at the development of selective estrogen receptor modulators (SERMs), tetrahydroisoquinoline derivative 27 was discovered by high throughput screening. Successive replacements of the p-F substituent of 27 by an aminoethoxy side chain and of the 1-H of the tetrahydroisoquinoline core by a 1-Me group provided analogues 19 and 20. These compounds showed potencies in a cell-based reporter gene assay (ERE assay) varying between 0.6 and 20 nM and displayed antagonist behaviors in the MCF-7 human breast adenocarcinoma cell line with IC(50)s in the range of 2-36 nM. The effect of N-phenyl substituents on the activity and pharmacokinetic properties of tetrahydroisoquinoline analogues was explored. As a result of this investigation, two potent derivatives bearing a p-F N-aryl group, 19c and 20c, were discovered as candidates suitable for further profiling. To gain insight into the ligand-receptor interaction, the X-ray crystallographic structure of the 1-H tetrahydroisoquinoline derivative (R)-18a in complex with ERalpha-ligand binding domain (LBD)(301-553)/C-->S triple mutant was solved to 2.28 Angstrom. An overlay of this X-ray crystal structure with that reported for the complex of ERalpha-LBD301-553/carboxymethylated C and raloxifene (5) shows that both compounds bind to the same cleft of the receptor and display comparable binding modes, with differences being observed in the conformation of their "D-ring" phenyl groups.