2-(3-(cyclopropylmethoxy)phenyl)acetic acid | 1247920-77-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: 2-(3-(cyclopropylmethoxy)phenyl)acetic acid
• 英文别名: 3-cyclopropylmethyloxyphenylacetic acid；(3-Cyclopropylmethoxy-phenyl)-acetic acid；2-[3-(cyclopropylmethoxy)phenyl]acetic acid
• CAS: 1247920-77-9
• 化学式: C₁₂H₁₄O₃
• 分子量: 206.241
• InChiKey: BHTUBVZDBCKLFO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  15
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  46.5
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  2-(3-(cyclopropylmethoxy)phenyl)acetic acid 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 N,N-二异丙基乙胺 作用下， 以 乙酸酐 、 N,N-二甲基甲酰胺 为溶剂， 反应 4.0h， 生成 methyl-3-(E)-(4-(3-(cyclopropylamino)-2-(4-fluorophenyl)-3-oxoprop-1-en-1-yl)phenyl)acrylate
  参考文献：
  名称：

  Orally available stilbene derivatives as potent HDAC inhibitors with antiproliferative activities and antitumor effects in human tumor xenografts

  摘要：

  Herein we report the synthesis and activity of a novel class of HDAC inhibitors based on 2, 3-diphenyl acrylic acid derivatives. The compounds in this series have shown to be potent HDAC inhibitors possessing significant antiproliferative activity. Further compounds in this series were subjected to metabolic stability in human liver microsomes (HLM), mouse liver microsomes (MLM), and exhibits promising stability in both. These efforts culminated with the identification of a developmental candidate (5a), which displayed desirable PK/PD relationships, significant efficacy in the xenograft models and attractive ADME profiles. (C) 2015 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2015.11.014
• 作为产物：
  描述：

  3-羟基苯乙酸 、 溴甲基环丙烷 在 potassium iodide 、 potassium hydroxide 作用下， 以 乙醇 为溶剂， 反应 18.0h， 以59%的产率得到2-(3-(cyclopropylmethoxy)phenyl)acetic acid
  参考文献：
  名称：

  Glucosylceramide synthase inhibitors

  摘要：

  该发明涉及对葡萄糖鞘氨醇合成酶（GCS）的抑制剂，用于治疗代谢性疾病，如溶酶体贮积病，可以单独使用或与酶替代疗法结合使用，并用于癌症的治疗。

  公开号：

  US09126993B2

文献信息

• GLUCOSYLCERAMIDE SYNTHASE INHIBITORS
  申请人：Genzyme Corporation

  公开号：US20140371460A1

  公开（公告）日：2014-12-18

  The invention relates to inhibitors of glucosylceramide synthase (GCS) useful for the treatment metabolic diseases, such as lysosomal storage diseases, either alone or in combination with enzyme replacement therapy, and for the treatment of cancer.

  本发明涉及一种对糖脂合成酶（GCS）的抑制剂，用于治疗代谢性疾病，例如溶酶体贮存病，可单独使用或与酶替代治疗相结合，并用于治疗癌症。
• Effect of Plasma Protein Binding on in Vivo Activity and Brain Penetration of Glycine/NMDA Receptor Antagonists
  作者：Michael Rowley、Janusz J. Kulagowski、Alan P. Watt、Denise Rathbone、Graeme I. Stevenson、Robert W. Carling、Raymond Baker、George R. Marshall、John A. Kemp、Alan C. Foster、Sarah Grimwood、Richard Hargreaves、Catherine Hurley、Kay L. Saywell、Mark D. Tricklebank、Paul D. Leeson

  DOI：10.1021/jm970417o

  日期：1997.12.1

  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.
• US20140255381A1
  申请人：——

  公开号：——

  公开（公告）日：——
• US9139580B2
  申请人：——

  公开号：US9139580B2

  公开（公告）日：2015-09-22
• US9126993B2
  申请人：——

  公开号：US9126993B2

  公开（公告）日：2015-09-08