7-chloro-4-hydroxy-3-(3-methylindol-1-yl)-2(1H)quinolone

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: 7-chloro-4-hydroxy-3-(3-methylindol-1-yl)-2(1H)quinolone
• 英文别名: 7-chloro-4-hydroxy-3-(3-methylindol-1-yl)-1H-quinolin-2-one
• 化学式: C₁₈H₁₃ClN₂O₂
• 分子量: 324.766
• InChiKey: ATEWLEZRFVYAKJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  23
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  54.3
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为产物：
  描述：

  甲基2-胺-4-氯苯酚酯 在 双(2-氧代-3-恶唑烷基)次磷酰氯 、 双(三甲基硅烷基)氨基钾 、 三乙胺 作用下， 以 四氢呋喃 、 1,2-二氯乙烷 、 甲苯 为溶剂， 反应 19.0h， 生成 7-chloro-4-hydroxy-3-(3-methylindol-1-yl)-2(1H)quinolone
  参考文献：
  名称：

  Effect of Plasma Protein Binding on in Vivo Activity and Brain Penetration of Glycine/NMDA Receptor Antagonists

  摘要：

  A major issue in designing drugs as antagonists at the glycine site of the NMDA receptor has been to achieve good in vivo activity. A series of 4-hydroxyquinolone glycine antagonists was found to be active in the DBA/2 mouse anticonvulsant assay, but improvements in in vitro affinity were not mirrored by corresponding increases in anticonvulsant activity. Here we show that binding of the compounds to plasma protein limits their brain penetration. Relative binding to the major plasma protein, albumin, was measured in two different ways: by a radioligand binding experiment or using an HPLC assay, for a wide structural range of glycine/NMDA site ligands. These measures of plasma protein binding correlate well (r = 0.84), and the HPLC assay has been used extensively to quantify plasma protein binding. For the 4-hydroxyquinolone series, binding to plasma protein correlates (r = 0.92) with log P (octanol/pH 7.4 buffer) over a range of log P values from 0 to 5. The anticonvulsant activity increases with in vitro affinity, but the slope of a plot of pED(50) versus pIC(50) is low (0.40); taking plasma protein binding into account in this plot increases the slope to 0.60. This shows that binding to albumin in plasma reduces the amount of compound free to diffuse across the blood-brain barrier. Further evidence comes from three other experiments: (a) Direct measurements of brain/blood ratios for three compounds (2, 16, 26) show the ratio decreases with increasing log P. (b) Warfarin, which competes for albumin binding sites dose-dependently, decreased the ED50 of 26 for protection against seizures induced by NMDLA. (c) Direct measurement of brain penetration using an in situ brain perfusion model in rat to measure the amount of drug crossing the blood/brain barrier showed that compounds 2, 26, and 32 penetrate the brain well in the absence of plasma protein, but this is greatly reduced when the drug is delivered in plasma. In the 4-hydroxyquinolones glycine site binding affinity increases with lipophilicity of the 3-substituent up to a maximum at a log P around 3, then does not improve further. When combined with increasing protein binding, this gives a parabolic relationship between predicted in vivo activity and log P, with a maximum log P value of 2.39. Finally, the plasma protein binding studies have been extended to other series of glycine site antagonists, and it is shown that for a. given log P these have similar protein binding to the 4-hydroxyquinolones, except for compounds that are not acidic. The results have implications for the design of novel glycine site antagonists, and it is suggested that it is necessary to either keep log P low or pK(a) high to obtain good central nervous system activity.

  DOI：

  10.1021/jm970417o

文献信息

• Hydroxyquinolone derivatives
  申请人：MERCK SHARP & DOHME LTD.

  公开号：EP0489458A1

  公开（公告）日：1992-06-10

  A class of 4-hydroxy-2(1H)-quinolone derivatives, substituted at the 3-position by an N-linked heteroaromatic ring system, are selective non-competitive antagonists of NMDA receptors and/or are antagonists of AMPA receptors, and are therefore of utility in the treatment of conditions, such as neurodegenerative disorders, convulsions or schizophrenia, which require the administration of an NMDA and or AMPA receptor antagonist.

  一类 4-羟基-2(1H)-喹诺酮衍生物在 3 位被 N-连接的杂芳香族环系统取代，是 NMDA 受体的选择性非竞争性拮抗剂和/或 AMPA 受体的拮抗剂，因此可用于治疗需要服用 NMDA 和/或 AMPA 受体拮抗剂的疾病，如神经退行性疾病、惊厥或精神分裂症。
• US5252584A
  申请人：——

  公开号：US5252584A

  公开（公告）日：1993-10-12