2-(4-(4-hydroxy-3-isopropyl-5-((4-nitrophenyl)ethynyl)benzyl)-3,5-dimethylphenoxy)acetic acid | 447415-26-1

• 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: 2-(4-(4-hydroxy-3-isopropyl-5-((4-nitrophenyl)ethynyl)benzyl)-3,5-dimethylphenoxy)acetic acid
• 英文别名: {4-[4-hydroxy-3-isopropyl-5-(4-nitrophenylethynyl)benzyl]-3,5-dimethylphenoxy}acetic acid；NH-3；Acetic acid, (4-((4-hydroxy-3-(1-methylethyl)-5-((4-nitrophenyl)ethynyl)phenyl)methyl)-3,5-dimethylphenoxy)-；2-[4-[[4-hydroxy-3-[2-(4-nitrophenyl)ethynyl]-5-propan-2-ylphenyl]methyl]-3,5-dimethylphenoxy]acetic acid
• CAS: 447415-26-1
• 化学式: C₂₈H₂₇NO₆
• 分子量: 473.525
• InChiKey: IXMROOKFPWGDGF-UHFFFAOYSA-N

物化性质

• 熔点：
  173-174 °C
• 沸点：
  679.5±55.0 °C(Predicted)
• 密度：
  1.30±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  6.8
• 重原子数：
  35
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  113
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  甲胺 、 2-(4-(4-hydroxy-3-isopropyl-5-((4-nitrophenyl)ethynyl)benzyl)-3,5-dimethylphenoxy)acetic acid 在 N,N'-羰基二咪唑 作用下， 以 四氢呋喃 为溶剂， 反应 18.0h， 以52%的产率得到2-(4-(4-hydroxy-3-isopropyl-5-((4-nitrophenyl)ethynyl)-benzyl)-3,5-dimethylphenoxy)-N-methylacetamide
  参考文献：
  名称：

  A CNS-Targeting Prodrug Strategy for Nuclear Receptor Modulators

  摘要：

  The blood-brain barrier is a major impediment for targeted central nervous system (CNS) therapeutics, especially with carboxylic acid-containing drugs. Nuclear receptor modulators, which often feature carboxylic acid motifs for target engagement, have emerged as a class of potentially powerful therapeutics for neurodegenerative CNS diseases. Herein is described a prodrug strategy that directs the biodistribution of parent drug nuclear receptor modulators into the CNS while masking them as functional receptor ligands in the periphery. This prodrug strategy targets a specific amidase, fatty acid amide hydrolase (FAAH), an enzyme with enriched expression in the CNS. Our results demonstrate that this prodrug strategy can be generalized to a variety of carboxylic acid-containing drug structures that satisfy the structural requirements of blood-brain barrier diffusion and FAAH substrate recognition.

  DOI：

  10.1021/acs.jmedchem.0c00868
• 作为产物：
  描述：

  异丙苯酚 在 盐酸 、 bis-triphenylphosphine-palladium(II) chloride 、 copper(l) iodide 、 lithium hydroxide monohydrate 、 palladium on activated charcoal 、 四丁基氟化铵 、 氢气 、 溴 、 一氯化碘 、 caesium carbonate 、 magnesium 、 溶剂黄146 、 三乙胺 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 133.5h， 生成 2-(4-(4-hydroxy-3-isopropyl-5-((4-nitrophenyl)ethynyl)benzyl)-3,5-dimethylphenoxy)acetic acid
  参考文献：
  名称：

  追逐 THR 拮抗剂 NH-3 难以捉摸的苯并呋喃杂质：合成、同位素标记和生物活性

  摘要：

  我们已经合成并确定了在 NH-3 合成过程中形成的一种长期怀疑但迄今为止未知的苯并呋喃副产物 (EBI) 的结构。了解其形成机制已启用同位素 (D) 标记。我们进一步开发了一种从 NH-3 中分离 EBI 的高效方法。有趣的是，EBI 被发现是一种非常有效的甲状腺激素受体 (THR) 激动剂，而 NH-3 是一种拮抗剂。在这个过程中，我们还实现了 NH-3 合成的显着改进。

  DOI：

  10.1021/acs.joc.5b02665

文献信息

• New synthetic routes to thyroid hormone analogs: d6-sobetirome, 3H-sobetirome, and the antagonist NH-3
  作者：Andrew T. Placzek、Thomas S. Scanlan

  DOI：10.1016/j.tet.2015.05.049

  日期：2015.9

  New synthetic routes for the preparation of isotopically labeled versions of thyroid hormone agonist sobetirome were developed using Knochel's iodine–magnesium exchange. A more efficient synthesis of the thyroid hormone antagonist NH-3 was developed from a common intermediate in the sobetirome route. Using the new synthetic routes, d6-and 3H-sobetirome were prepared for their use in studying biodistribution

  利用Knochel的碘-镁交换，开发了制备同位素标记版本的甲状腺激素激动剂sobetirome的新合成途径。甲状腺激素拮抗剂NH-3的合成更有效，它是由茄脂酶途径中的一种常见中间体制成的。使用新的合成途径，制备了d 6-和3 H-糖异位症，以用于研究sobetirome的生物分布和细胞吸收。通往NH-3的新途径可实现更快，更有效的合成，并提供先进的中间体，以促进在最终形成键的合成步骤中产生拮抗剂类似物。
• An Improved Synthesis of (4-{4-Hydroxy-3-isopropyl-5-[(4-nitrophenyl)ethynyl]benzyl}-3,5-dimethylphenoxy)acetic Acid (NH-3)
  作者：Kenneth Rehder、Madathil Gopinathan

  DOI：10.1055/s-0028-1088041

  日期：——

  5-dimethylphenoxy)acetate in high yield. Saponification of the ester group, followed by the removal of the methoxymethyl group afforded (4-4-hydroxy-3-isopropyl-5-[(4-nitrophenyl)ethynyl]benzyl}-3,5-dimethylphenoxy)acetic acid (NH-3). coupling - Sonogashira coupling - palladium catalysis - 1-iodo-4-nitrobenzene - hydrolysis

  将4- [3-碘-5-异丙基-4-（甲氧基甲氧基）苄基] -3，5-二甲基苯氧基}乙酸甲酯与（三甲基甲硅烷基）乙炔的Sonogashira偶联，以定量收率得到相应的（三甲基甲硅烷基）乙炔基衍生物。该中间体与1-碘-4-硝基苯的无铜钯催化偶联得到甲基（4- 3-异丙基-4-（甲氧基甲氧基）-5-[（4-硝基苯基）乙炔基]苄基} -3,5 -高产率的-二甲基苯氧基）乙酸酯。酯化酯基，然后除去甲氧基甲基，得到（4- 4-羟基-3-异丙基-5-[（4-硝基苯基）乙炔基]苄基} -3,5-二甲基苯氧基）乙酸（NH -3）。 偶联-Sonogashira偶联-钯催化-1-碘-4-硝基苯-水解
• Rational Design and Synthesis of a Novel Thyroid Hormone Antagonist That Blocks Coactivator Recruitment
  作者：Ngoc-Ha Nguyen、James W. Apriletti、Suzana T. Cunha Lima、Paul Webb、John D. Baxter、Thomas S. Scanlan

  DOI：10.1021/jm0201013

  日期：2002.7.1

  Recent efforts have focused on the design and synthesis of thyroid hormone (T-3) antagonists as potential therapeutic agents and chemical probes to understand hormone-signaling pathways. We previously reported the development of novel first-generation T-3 antagonists DIBRT, HY-4, and GC-14 using the "extension hypothesis" as a general guideline in hormone antagonist design.(1-3) These compounds contain extensions at the 5'-position (DIBRT, GC-14) of the outer thyronine ring or from the bridging carbon (HY-4). All of these compounds have only a modest affinity and potency for the thyroid hormone receptor (TR) that limits studies of their antagonistic actions. Here, we report the design and synthesis of a novel series of 5'-phenylethynyl derivatives sharing the GC-1 halogen-free thyronine scaffold.(4) One compound (NH-3) is a T-3 antagonist with negligible TR agonist activity and improved TR binding affinity and potency that allow for further characterization of its observed activity. One mechanism for antagonism appears to be the ability of NH-3 to block TR-coactivator interactions. NH-3 will be a useful pharmacological tool for further study of T-3 signaling and TR function.
• Compositions For Treating Retinal Degeneration And Methods of Production and Use Thereof
  申请人：THE BOARD OF REGENTS OF THE UNIVERSITY OF OKLAHOMA

  公开号：US20170007589A1

  公开（公告）日：2017-01-12

  Compositions for use in methods of treating and/or inhibiting a pathologic ocular condition, as well as methods of producing and using same, are disclosed.
• [EN] COMPOSITIONS FOR TREATING RETINAL DEGENERATION AND METHODS OF PRODUCTION AND USE THEREOF<br/>[FR] COMPOSITIONS POUR LE TRAITEMENT DE LA DÉGÉNÉRESCENCE RÉTINIENNE ET MÉTHODES DE PRODUCTION ET D'UTILISATION DE CELLES-CI
  申请人：UNIV OKLAHOMA

  公开号：WO2015120115A1

  公开（公告）日：2015-08-13

  Compositions for use in methods of treating and/or inhibiting a pathologic ocular condition, as well as methods of producing and using same, are disclosed.