| 1562372-47-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并硫氮卓类
• CAS: 1562372-47-7
• 化学式: C₄₈H₅₆N₆O₆S₂
• 分子量: 877.141
• InChiKey: DCJGBWGKFUWBHQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.39
• 重原子数：
  62.0
• 可旋转键数：
  17.0
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  108.74
• 氢给体数：
  0.0
• 氢受体数：
  14.0

反应信息

• 作为产物：
  描述：

  己二酸 、 喹硫平 在 4-二甲氨基吡啶 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 12.33h， 生成
  参考文献：
  名称：

  Reversible Dimers of the Atypical Antipsychotic Quetiapine Inhibit P-Glycoprotein-Mediated Efflux in Vitro with Increased Binding Affinity and in Situ at the Blood-Brain Barrier

  摘要：

  The multidrug resistance transporter P-glycoprotein (P-gp) is highly expressed in the capillary endothelial cells of the blood-brain barrier (BBB) where it functions to limit the brain penetration of many drugs, including antipsychotic agents used to treat schizophrenia. Therefore, in an effort to inhibit the transporter, we designed dimers of the antipsychotic drug and P-gp substrate quetiapine (QT), linked by variable length tethers. In P-gp overexpressing cells and in human brain capillary endothelial hCMEC/D3 cells, the dimer with the shortest tether length(QT(2)C(2)) (1) was the most potent inhibitor showing >80-fold better inhibition of P-gp-mediated transport than monomeric QT. The dimers, which are linked via ester moieties, are designed to revert to the therapeutic monomer once inside the target cells. We demonstrated that the addition of two sterically blocking methyl groups to the linker (QT(2)C(2)Me(2), 8) increased the half-life of the molecule in plasma 10-fold as compared to the dimer lacking methyl groups (QT(2)C(2), 1), while retaining inhibitory potency for P-gp transport and sensitivity to cellular esterases. Experiments with purified P-gp demonstrated that QT(2)C2 (1) and QT(2)C(2)Me(2) (8) interacted with both the H- and R-binding sites of the tra(n)sporter with binding affinities 20- to 30-fold higher than that of monomeric QT. Using isolated rat brain capillaries, QT(2)C(2)Me(2) (8) was a more potent inhibitor of P-gp transport than QT. Lastly, we showed that QT(2)C(2)Me(2) (8) increased the accumulation of the P-gp substrate verapamil in rat brain in situ three times more than QT. Together, these results indicate that the QT dimer QT(2)C(2)Me(2) (8) strongly inhibited P-gp transport activity in human brain capillary endothelial cells, in rat brain capillaries, and at the BBB in an animal model.

  DOI：

  10.1021/cn4002329