methyl ­2-­methyl-­2-­(3-­phenoxyphenyl)propanoate | 730977-73-8

• 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: methyl ­2-­methyl-­2-­(3-­phenoxyphenyl)propanoate
• 英文别名: methyl 2-methyl-2-(3-phenoxyphenyl)propanoate；Methyl 2-methyl-2-(3-phenoxy-phenyl)-propionate
• CAS: 730977-73-8
• 化学式: C₁₇H₁₈O₃
• 分子量: 270.328
• InChiKey: WJOUCFICUSBYTM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  20
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  35.5
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  methyl ­2-­methyl-­2-­(3-­phenoxyphenyl)propanoate 在 potassium trimethylsilonate 作用下， 以 四氢呋喃 为溶剂， 反应 2.0h， 以95%的产率得到2-methyl-2-(3-phenoxyphenyl)propanoic acid
  参考文献：
  名称：

  Substrate-Selective Inhibition of Cyclooxygenase-2: Development and Evaluation of Achiral Profen Probes

  摘要：

  Cyclooxygenase-2 (COX-2) oxygenates arachidonic acid and the endocannabinoids 2-arachidonoylglycerol (2-AG) and arachidonoylethanolamide (AEA). We recently reported that (R)-profens selectively inhibit endocannabinoid oxygenation but not arachidonic acid oxygenation. In this work, we synthesized achiral derivatives of five profen scaffolds and evaluated them for substrate-selective inhibition using in vitro and cellular assays. The size of the substituents dictated the inhibitory strength of the analogs, with smaller substituents enabling greater potency but less selectivity. Inhibitors based on the flurbiprofen scaffold possessed the greatest potency and selectivity, with desmethylflurbiprofen (3a) exhibiting an IC50 of 0.11 mu M for inhibition of 2-AG oxygenation. The crystal structure of desmethylflurbiprofen complexed to mCOX-2 demonstrated a similar binding mode to other profens. Desmethylflurbiprofen exhibited a half-life in mice comparable to that of ibuprofen. The data presented suggest that achiral profens can act as lead molecules toward in vivo probes of substrate-selective COX-2 inhibition.

  DOI：

  10.1021/ml3001616
• 作为产物：
  描述：

  3-(4-苯氧基苯基)丙酸 在 硫酸 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 为溶剂， 反应 4.0h， 生成 methyl ­2-­methyl-­2-­(3-­phenoxyphenyl)propanoate
  参考文献：
  名称：

  Substrate-Selective Inhibition of Cyclooxygenase-2: Development and Evaluation of Achiral Profen Probes

  摘要：

  Cyclooxygenase-2 (COX-2) oxygenates arachidonic acid and the endocannabinoids 2-arachidonoylglycerol (2-AG) and arachidonoylethanolamide (AEA). We recently reported that (R)-profens selectively inhibit endocannabinoid oxygenation but not arachidonic acid oxygenation. In this work, we synthesized achiral derivatives of five profen scaffolds and evaluated them for substrate-selective inhibition using in vitro and cellular assays. The size of the substituents dictated the inhibitory strength of the analogs, with smaller substituents enabling greater potency but less selectivity. Inhibitors based on the flurbiprofen scaffold possessed the greatest potency and selectivity, with desmethylflurbiprofen (3a) exhibiting an IC50 of 0.11 mu M for inhibition of 2-AG oxygenation. The crystal structure of desmethylflurbiprofen complexed to mCOX-2 demonstrated a similar binding mode to other profens. Desmethylflurbiprofen exhibited a half-life in mice comparable to that of ibuprofen. The data presented suggest that achiral profens can act as lead molecules toward in vivo probes of substrate-selective COX-2 inhibition.

  DOI：

  10.1021/ml3001616

文献信息

• Geminallyl di-substituted nsaid derivatives as abeta 42 lowering agents
  申请人：Munoz Benito

  公开号：US20060063937A1

  公开（公告）日：2006-03-23

  The present invention encompasses compounds of Formula I (I) or pharmaceutically acceptable salts thereof, wherein A is the base molecule of a propionic acid or acetic acid NSAID, or a derivative thereof, X is —CO 2 H, 1H-tetrazol-5-yl or 2H-tetrazol-5-yl and R 1 and R 2 are each independently selected from the group consisting of: C 1-6 alkyl and C 3-6 cycloalkyl, as well as pharmaceutical composition comprising said compounds and methods of using said compounds. The compounds of the present invention lower the level of Aβ 42 and are therefore useful for preventing, delaying or reversing the progression of Alzheimer s Disease.

  本发明涵盖公式I（I）的化合物或其药学上可接受的盐，其中A是丙酸或乙酸非甾体抗炎药的基本分子或其衍生物，X为-CO2H，1H-四唑-5-基或2H-四唑-5-基，R1和R2各自独立地选自以下组：C1-6烷基和C3-6环烷基，以及包括所述化合物的制药组合物和使用所述化合物的方法。本发明的化合物降低Aβ42的水平，因此有助于预防、延缓或逆转阿尔茨海默病的进展。
• Geminally di-substituted NSAID derivatives as Aβ42 lowering agents
  申请人：Merck + Co., Inc.

  公开号：US07332516B2

  公开（公告）日：2008-02-19

  The present invention encompasses compounds of Formula I (I) or pharmaceutically acceptable salts thereof, wherein A is the base molecule of a propionic acid or acetic acid NSAID, or a derivative thereof, X is —CO2H, 1H-tetrazol-5-yl or 2H-tetrazol-5-yl and R1 and R2 are each independently selected from the group consisting of: C1-6alkyl and C3-6cycloalkyl, as well as pharmaceutical composition comprising said compounds and methods of using said compounds. The compounds of the present invention lower the level of Aβ42 and are therefore useful for preventing, delaying or reversing the progression of Alzheimer's Disease.

  本发明涵盖了式I（I）的化合物或其药学上可接受的盐，其中A是丙酸或乙酸NSAID的基本分子或其衍生物，X是-CO2H，1H-四唑-5-基或2H-四唑-5-基，R1和R2各自独立地选自以下群体：C1-6烷基和C3-6环烷基，以及包括所述化合物的制药组合物和使用所述化合物的方法。本发明的化合物降低Aβ42的水平，因此对于预防、延缓或逆转阿尔茨海默病的进展是有用的。
• The geminal dimethyl analogue of Flurbiprofen as a novel Aβ42 inhibitor and potential Alzheimer’s disease modifying agent
  作者：Nicholas Stock、Benito Munoz、Jonathan D.J. Wrigley、Mark S. Shearman、Dirk Beher、James Peachey、Toni L. Williamson、Gretchen Bain、Weichao Chen、Xiaohui Jiang、René St-Jacques、Peppi Prasit

  DOI：10.1016/j.bmcl.2006.01.033

  日期：2006.4

  The subtle modification of a selection of A beta(42) inhibiting non-steroidal anti-inflammatory drugs (NSAIDs), through synthesis of the geminal dimethyl analogues, was anticipated to ablate their cyclooxygenase activity whilst maintaining A beta(42) inhibition. Methylflurbiprofen 6 exhibited similar in vitro A beta(42) inhibition to its parent NSAID Flurbiprofen and was further evaluated in the Tg2576 mouse model of Alzheimer's disease and an animal model of gastro-intestinal (GI) impairment, but proved unviable for further clinical development. (C) 2006 Elsevier Ltd. All rights reserved.
• EP1587798A4
  申请人：——

  公开号：EP1587798A4

  公开（公告）日：2007-06-27
• GEMINALLY DI-SUBSTITUTED NSAID DERIVATIVES AS ABETA 42 LOWERING AGENTS
  申请人：Merck & Co., Inc.

  公开号：EP1587798A2

  公开（公告）日：2005-10-26