4-[4-(2,4-dioxothiazolidin-5-ylidenemethyl)-2-methoxyphenoxy]-2-trifluoromethylbenzoic acid methyl ester | 873927-78-7

• 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-[4-(2,4-dioxothiazolidin-5-ylidenemethyl)-2-methoxyphenoxy]-2-trifluoromethylbenzoic acid methyl ester
• 英文别名: Methyl 4-[4-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-2-methoxyphenoxy]-2-(trifluoromethyl)benzoate；methyl 4-[4-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-2-methoxyphenoxy]-2-(trifluoromethyl)benzoate
• CAS: 873927-78-7
• 化学式: C₂₀H₁₄F₃NO₆S
• 分子量: 453.395
• InChiKey: CKVDHQAVOASGLY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  31
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  116
• 氢给体数：
  1
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  4-[4-(2,4-dioxothiazolidin-5-ylidenemethyl)-2-methoxyphenoxy]-2-trifluoromethylbenzoic acid methyl ester 在 sodium tetrahydroborate 、 cobalt(II) chloride hexahydrate 、 二甲基乙二醛肟 、 sodium hydroxide 作用下， 以 四氢呋喃 、 水 、 N,N-二甲基甲酰胺 为溶剂， 以83%的产率得到4-[4-(2,4-dioxothiazolidin-5-ylmethyl)-2-methoxyphenoxy]-2-trifluoromethylbenzoic acid methyl ester
  参考文献：
  名称：

  Identification of Diaryl Ether-Based Ligands for Estrogen-Related Receptor α as Potential Antidiabetic Agents

  摘要：

  Estrogen-related receptor a (ERR alpha) is an orphan nuclear receptor that has been functionally implicated in the regulation of energy homeostasis. Herein is described the development of diaryl ether based thiazolidenediones, which function as selective ligands against this receptor. Series optimization provided several potent analogues that inhibit the recruitment of a coactivator peptide fragment in in vitro biochemical assays (IC50 < 150 nM) and cellular two-hybrid reporter assays against the ligand binding domain (IC50 = 1-5 mu M). A cocrystal structure of the ligand-binding domain of ERR alpha with lead compound 29 revealed the presence of a covalent interaction between the protein and ligand, which has been shown to be reversible. In diet-induced murine models of obesity and in an overt diabetic rat model, oral administration of 29 normalized insulin and circulating triglyceride levels, improved insulin sensitivity, and was body weight neutral. This provides the first demonstration of functional activities of an ERRa ligand in metabolic animal models.

  DOI：

  10.1021/jm101063h
• 作为产物：
  描述：

  4-氟-2-(三氟甲基)苯甲酸甲酯 在 ammonium acetate 、 potassium carbonate 、 溶剂黄146 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 5.0h， 生成 4-[4-(2,4-dioxothiazolidin-5-ylidenemethyl)-2-methoxyphenoxy]-2-trifluoromethylbenzoic acid methyl ester
  参考文献：
  名称：

  Identification of Diaryl Ether-Based Ligands for Estrogen-Related Receptor α as Potential Antidiabetic Agents

  摘要：

  Estrogen-related receptor a (ERR alpha) is an orphan nuclear receptor that has been functionally implicated in the regulation of energy homeostasis. Herein is described the development of diaryl ether based thiazolidenediones, which function as selective ligands against this receptor. Series optimization provided several potent analogues that inhibit the recruitment of a coactivator peptide fragment in in vitro biochemical assays (IC50 < 150 nM) and cellular two-hybrid reporter assays against the ligand binding domain (IC50 = 1-5 mu M). A cocrystal structure of the ligand-binding domain of ERR alpha with lead compound 29 revealed the presence of a covalent interaction between the protein and ligand, which has been shown to be reversible. In diet-induced murine models of obesity and in an overt diabetic rat model, oral administration of 29 normalized insulin and circulating triglyceride levels, improved insulin sensitivity, and was body weight neutral. This provides the first demonstration of functional activities of an ERRa ligand in metabolic animal models.

  DOI：

  10.1021/jm101063h

文献信息

• Identification of Diaryl Ether-Based Ligands for Estrogen-Related Receptor α as Potential Antidiabetic Agents
  作者：Raymond J. Patch、Lily L. Searle、Alexander J. Kim、Debyendu De、Xizhen Zhu、Hossein B. Askari、John C. O’Neill、Marta C. Abad、Dionisios Rentzeperis、Jianying Liu、Michael Kemmerer、Ling Lin、Jyotsna Kasturi、John G. Geisler、James M. Lenhard、Mark R. Player、Micheal D. Gaul

  DOI：10.1021/jm101063h

  日期：2011.2.10

  Estrogen-related receptor a (ERR alpha) is an orphan nuclear receptor that has been functionally implicated in the regulation of energy homeostasis. Herein is described the development of diaryl ether based thiazolidenediones, which function as selective ligands against this receptor. Series optimization provided several potent analogues that inhibit the recruitment of a coactivator peptide fragment in in vitro biochemical assays (IC50 < 150 nM) and cellular two-hybrid reporter assays against the ligand binding domain (IC50 = 1-5 mu M). A cocrystal structure of the ligand-binding domain of ERR alpha with lead compound 29 revealed the presence of a covalent interaction between the protein and ligand, which has been shown to be reversible. In diet-induced murine models of obesity and in an overt diabetic rat model, oral administration of 29 normalized insulin and circulating triglyceride levels, improved insulin sensitivity, and was body weight neutral. This provides the first demonstration of functional activities of an ERRa ligand in metabolic animal models.