{4-[3-(4-aminophenylethynyl)-5-isopropyl-4-methoxymethoxybenyl]-3,5-dimethylphenoxy}acetic acid methyl ester | 446312-37-4

• 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: {4-[3-(4-aminophenylethynyl)-5-isopropyl-4-methoxymethoxybenyl]-3,5-dimethylphenoxy}acetic acid methyl ester
• 英文别名: {4-[3-(4-aminophenylethynyl)-5-isopropyl-4-methoxymethoxybenzyl]-3,5-dimethylphenoxy}acetic acid methyl ester；Methyl 2-[4-[[3-[2-(4-aminophenyl)ethynyl]-4-(methoxymethoxy)-5-propan-2-ylphenyl]methyl]-3,5-dimethylphenoxy]acetate
• CAS: 446312-37-4
• 化学式: C₃₁H₃₅NO₅
• 分子量: 501.623
• InChiKey: FUJXDHUPRXYKCO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.9
• 重原子数：
  37
• 可旋转键数：
  12
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  80
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  {4-[3-(4-aminophenylethynyl)-5-isopropyl-4-methoxymethoxybenyl]-3,5-dimethylphenoxy}acetic acid methyl ester 在 间氯过氧苯甲酸 作用下， 以 氯仿 为溶剂， 反应 3.0h， 以61%的产率得到{4-[3-isopropyl-4-methoxymethoxy-5-(4-nitrophenylethynyl)benzyl]-3,5-dimethylphenoxy}acetic acid methyl ester
  参考文献：
  名称：

  Rational Design and Synthesis of a Novel Thyroid Hormone Antagonist That Blocks Coactivator Recruitment

  摘要：

  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.

  DOI：

  10.1021/jm0201013
• 作为产物：
  描述：

  [4-(3-isopropyl-4-methoxymethoxybenzyl)-3,5-dimethylphenoxy]acetic acid methyl ester 在 盐酸 、 一氯化碘 、 双(三甲基硅烷基)氨基钾 、 caesium carbonate 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 23.5h， 生成 {4-[3-(4-aminophenylethynyl)-5-isopropyl-4-methoxymethoxybenyl]-3,5-dimethylphenoxy}acetic acid methyl ester
  参考文献：
  名称：

  选择性甲状腺激素受体调节剂的哈米特分析揭示了激素拮抗剂的结构和电子要求

  摘要：

  作为甲状腺激素受体 (TR) 的异构体选择性激动剂或拮抗剂的选择性甲状腺激素调节剂可能对与异常激素信号传导相关的疾病有治疗作用。迄今为止报道的最有效的甲状腺激素拮抗剂是 NH-3。为了探索 NH-3 的 5'-对硝基芳基部分的重要性并了解哪些化学特征对赋予拮抗作用很重要，我们试图扩展 5'-苯基乙炔基 GC-1 衍生物类的构效关系数据. 在此，我们描述了一种改进的合成路线，利用钯催化化学有效地获得一系列具有不同尺寸和电子特性的 5'-苯基乙炔基化合物。我们准备并测试了 16 种类似物的 TR 结合和反式激活活性。在 5' 位置替换减少绑定亲和力，但保留 TRbeta 选择性。在反式激活试验中，类似物显示出一系列激动剂、拮抗剂和混合激动剂/拮抗剂活性，这些活性与西格玛取代基值和 TR 调制之间的哈米特分析中的电子特征相关。类似物 NH-5、NH-7、NH-9、NH-11 和 NH-23 显示出完整的拮抗剂活性，但与

  DOI：

  10.1021/ja0440093

文献信息

• Hammett Analysis of Selective Thyroid Hormone Receptor Modulators Reveals Structural and Electronic Requirements for Hormone Antagonists
  作者：Ngoc-Ha Nguyen、James W. Apriletti、John D. Baxter、Thomas S. Scanlan

  DOI：10.1021/ja0440093

  日期：2005.4.1

  Selective thyroid hormone modulators that function as isoform-selective agonists or antagonists of the thyroid hormone receptors (TRs) might be therapeutically useful in diseases associated with aberrant hormone signaling. The most potent thyroid hormone antagonist reported to date is NH-3. To explore the significance of the 5'-p-nitroaryl moiety of NH-3 and understand what chemical features are important

  作为甲状腺激素受体 (TR) 的异构体选择性激动剂或拮抗剂的选择性甲状腺激素调节剂可能对与异常激素信号传导相关的疾病有治疗作用。迄今为止报道的最有效的甲状腺激素拮抗剂是 NH-3。为了探索 NH-3 的 5'-对硝基芳基部分的重要性并了解哪些化学特征对赋予拮抗作用很重要，我们试图扩展 5'-苯基乙炔基 GC-1 衍生物类的构效关系数据. 在此，我们描述了一种改进的合成路线，利用钯催化化学有效地获得一系列具有不同尺寸和电子特性的 5'-苯基乙炔基化合物。我们准备并测试了 16 种类似物的 TR 结合和反式激活活性。在 5' 位置替换减少绑定亲和力，但保留 TRbeta 选择性。在反式激活试验中，类似物显示出一系列激动剂、拮抗剂和混合激动剂/拮抗剂活性，这些活性与西格玛取代基值和 TR 调制之间的哈米特分析中的电子特征相关。类似物 NH-5、NH-7、NH-9、NH-11 和 NH-23 显示出完整的拮抗剂活性，但与
• 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.