3-[(3,3-difluoro-2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)methyl]-3,9-diazaspiro[5.5]undecane | 1179356-52-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 氮杂螺癸烷衍生物
• 英文名称: 3-[(3,3-difluoro-2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)methyl]-3,9-diazaspiro[5.5]undecane
• 英文别名: 3-[(3,3-Difluoro-2,2-dimethyl-1-benzofuran-7-yl)methyl]-3,9-diazaspiro[5.5]undecane
• CAS: 1179356-52-5
• 化学式: C₂₀H₂₈F₂N₂O
• 分子量: 350.452
• InChiKey: LHBUZLPCKOBPFB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  25
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.7
• 拓扑面积：
  24.5
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  5-氨基-2-吡啶羧酸 、 3-[(3,3-difluoro-2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)methyl]-3,9-diazaspiro[5.5]undecane 在 三乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 二氯甲烷 为溶剂， 反应 1.5h， 生成 (5-aminopyridin-2-yl)(9-((3,3-difluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methyl)-3,9-diazaspiro[5.5]undecan-3-yl)methanone 2,2,2-trifluoroacetate
  参考文献：
  名称：

  Increasing Selectivity of CC Chemokine Receptor 8 Antagonists by Engineering Nondesolvation Related Interactions with the Intended and Off-Target Binding Sites

  摘要：

  The metabolic stability and selectivity of a series of CCR8 antagonists against binding to the hERG ion channel and cytochrome Cyp2D6 are studied by principal component analysis. It is demonstrated that an efficient way of increasing metabolic stability and selectivity of this series is to decrease compound lipophilicity by engineering nondesolvation related attractive interactions with CCR8, as rationalized by three-dimensional receptor models. Although Such polar interactions led to increased compound selectivity, such a strategy could also jeopardize the DMPK profile of compounds. However, once increased potency is found, the lipophilicity can be readjusted by engineering hydrophobic substituents that fit to CCR8 but do not fit to hERG. Several such lipophilic fragments are identified by two-dimensional fragment-based QSAR analysis. Electrophysiological measurements and site-directed mutagenesis studies indicated that the repulsive interactions of these fragments with hERG are caused by steric hindrances with residue F656.

  DOI：

  10.1021/jm900713y
• 作为产物：
  描述：

  tert-butyl 9-[(3,3-difluoro-2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)methyl]-3,9-diazaspiro[5.5]undecane-3-carboxylate 在 盐酸 作用下， 以 甲醇 为溶剂， 反应 3.0h， 生成 3-[(3,3-difluoro-2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)methyl]-3,9-diazaspiro[5.5]undecane
  参考文献：
  名称：

  Increasing Selectivity of CC Chemokine Receptor 8 Antagonists by Engineering Nondesolvation Related Interactions with the Intended and Off-Target Binding Sites

  摘要：

  The metabolic stability and selectivity of a series of CCR8 antagonists against binding to the hERG ion channel and cytochrome Cyp2D6 are studied by principal component analysis. It is demonstrated that an efficient way of increasing metabolic stability and selectivity of this series is to decrease compound lipophilicity by engineering nondesolvation related attractive interactions with CCR8, as rationalized by three-dimensional receptor models. Although Such polar interactions led to increased compound selectivity, such a strategy could also jeopardize the DMPK profile of compounds. However, once increased potency is found, the lipophilicity can be readjusted by engineering hydrophobic substituents that fit to CCR8 but do not fit to hERG. Several such lipophilic fragments are identified by two-dimensional fragment-based QSAR analysis. Electrophysiological measurements and site-directed mutagenesis studies indicated that the repulsive interactions of these fragments with hERG are caused by steric hindrances with residue F656.

  DOI：

  10.1021/jm900713y

文献信息

• Increasing Selectivity of CC Chemokine Receptor 8 Antagonists by Engineering Nondesolvation Related Interactions with the Intended and Off-Target Binding Sites
  作者：Igor Shamovsky、Chris de Graaf、Lisa Alderin、Malena Bengtsson、Håkan Bladh、Lena Börjesson、Stephen Connolly、Hazel J. Dyke、Marco van den Heuvel、Henrik Johansson、Bo-Göran Josefsson、Anna Kristoffersson、Tero Linnanen、Annea Lisius、Roope Männikkö、Bo Nordén、Steve Price、Lena Ripa、Didier Rognan、Alexander Rosendahl、Marco Skrinjar、Klaus Urbahns

  DOI：10.1021/jm900713y

  日期：2009.12.10

  The metabolic stability and selectivity of a series of CCR8 antagonists against binding to the hERG ion channel and cytochrome Cyp2D6 are studied by principal component analysis. It is demonstrated that an efficient way of increasing metabolic stability and selectivity of this series is to decrease compound lipophilicity by engineering nondesolvation related attractive interactions with CCR8, as rationalized by three-dimensional receptor models. Although Such polar interactions led to increased compound selectivity, such a strategy could also jeopardize the DMPK profile of compounds. However, once increased potency is found, the lipophilicity can be readjusted by engineering hydrophobic substituents that fit to CCR8 but do not fit to hERG. Several such lipophilic fragments are identified by two-dimensional fragment-based QSAR analysis. Electrophysiological measurements and site-directed mutagenesis studies indicated that the repulsive interactions of these fragments with hERG are caused by steric hindrances with residue F656.