(+/-)-4-{2-[(3-cyclobutyloxy-4-difluoromethoxy)phenyl]-2-[4-(1-carbomethoxy)phenyl]ethyl}pyridine | 552287-72-6

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (+/-)-4-{2-[(3-cyclobutyloxy-4-difluoromethoxy)phenyl]-2-[4-(1-carbomethoxy)phenyl]ethyl}pyridine
• 英文别名: Methyl 4-[1-[3-cyclobutyloxy-4-(difluoromethoxy)phenyl]-2-pyridin-4-ylethyl]benzoate
• CAS: 552287-72-6
• 化学式: C₂₆H₂₅F₂NO₄
• 分子量: 453.486
• InChiKey: QWOYJPKCUOBTEG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.2
• 重原子数：
  33
• 可旋转键数：
  10
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  57.6
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (+/-)-4-{2-[(3-cyclobutyloxy-4-difluoromethoxy)phenyl]-2-[4-(1-carbomethoxy)phenyl]ethyl}pyridine 在 MMPP 作用下， 以 甲醇 、 乙醚 、 二氯甲烷 为溶剂， 反应 4.5h， 生成 2-[4-[1-[3-Cyclobutyloxy-4-(difluoromethoxy)phenyl]-2-(1-oxidopyridin-1-ium-4-yl)ethyl]phenyl]propan-2-ol
  参考文献：
  名称：

  Optimization of a Tertiary Alcohol Series of Phosphodiesterase-4 (PDE4) Inhibitors:  Structure−Activity Relationship Related to PDE4 Inhibition and Human Ether-a-go-go Related Gene Potassium Channel Binding Affinity

  摘要：

  A SAR study on the tertiary alcohol series of phosphodiesterase-4 (PDE4) inhibitors related to 1 is described. In addition to inhibitory potency against PDE4 and the lipopolysaccharide-induced production of TNFalpha in human whole blood, the binding affinity of these compounds for the human ether-a-go-go related gene (hERG) potassium channel (an in vitro measure for the potential to cause QTc prolongation) was assessed. Four key structural moieties in the molecule were studied, and the impact of the resulting modifications in modulating these activities was evaluated. From these studies, (+)-3d (L-869,298) was identified as an optimized structure with respect to PDE4 inhibitory potency, lack of binding affinity to the hERG potassium channel, and pharmacokinetic behavior. (+)-3d exhibited good in vivo efficacy in several models of pulmonary function with a wide therapeutic index with respect to emesis and prolongation of the QTc interval.

  DOI：

  10.1021/jm0204542
• 作为产物：
  描述：

  3-环丁基氧基-4-二氟甲氧基苯甲醛 在 吡啶 、 lithium hydroxide 、 potassium permanganate 、 正丁基锂 、 氯化亚砜 、 双(三甲基硅烷基)氨基钾 作用下， 以 四氢呋喃 、 甲醇 、 六甲基磷酰三胺 、 乙醚 、 正己烷 、 丙酮 、 甲苯 为溶剂， 反应 24.75h， 生成 (+/-)-4-{2-[(3-cyclobutyloxy-4-difluoromethoxy)phenyl]-2-[4-(1-carbomethoxy)phenyl]ethyl}pyridine
  参考文献：
  名称：

  Optimization of a Tertiary Alcohol Series of Phosphodiesterase-4 (PDE4) Inhibitors:  Structure−Activity Relationship Related to PDE4 Inhibition and Human Ether-a-go-go Related Gene Potassium Channel Binding Affinity

  摘要：

  A SAR study on the tertiary alcohol series of phosphodiesterase-4 (PDE4) inhibitors related to 1 is described. In addition to inhibitory potency against PDE4 and the lipopolysaccharide-induced production of TNFalpha in human whole blood, the binding affinity of these compounds for the human ether-a-go-go related gene (hERG) potassium channel (an in vitro measure for the potential to cause QTc prolongation) was assessed. Four key structural moieties in the molecule were studied, and the impact of the resulting modifications in modulating these activities was evaluated. From these studies, (+)-3d (L-869,298) was identified as an optimized structure with respect to PDE4 inhibitory potency, lack of binding affinity to the hERG potassium channel, and pharmacokinetic behavior. (+)-3d exhibited good in vivo efficacy in several models of pulmonary function with a wide therapeutic index with respect to emesis and prolongation of the QTc interval.

  DOI：

  10.1021/jm0204542