4-[2,6-Dibromo-4-(diethoxyphosphorylmethoxy)phenoxy]-2-propan-2-ylphenol | 1085957-39-6

• 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-[2,6-Dibromo-4-(diethoxyphosphorylmethoxy)phenoxy]-2-propan-2-ylphenol
• CAS: 1085957-39-6
• 化学式: C₂₀H₂₅Br₂O₆P
• 分子量: 552.197
• InChiKey: DUFJOESNZBBLOL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.7
• 重原子数：
  29
• 可旋转键数：
  10
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  74.2
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  4-[2,6-Dibromo-4-(diethoxyphosphorylmethoxy)phenoxy]-2-propan-2-ylphenol 在 三甲基溴硅烷 作用下， 以 二氯甲烷 为溶剂， 生成 [3,5-dibromo-4-(4'-hydroxy-3'-isopropylphenoxy)phenoxy]methylphosphonic acid
  参考文献：
  名称：

  Synthesis and Biological Evaluation of a Series of Liver-Selective Phosphonic Acid Thyroid Hormone Receptor Agonists and Their Prodrugs

  摘要：

  Phosphonic acid (PA) thyroid hormone receptor (TR) agonists were synthesized to exploit the poor distribution of PA-based drugs to extrahepatic tissues and thereby to improve the therapeutic index. Nine PAs showed excellent TR binding affinities (TR beta(1), K-i < 10 nM), and most of them demonstrated significant cholesterol lowering effects in a cholesterol-fed rat (CFR) model. Unlike the corresponding carboxylic acid analogue and T-3, PA 22c demonstrated liver-selective effects by inducing maximal mitochondrial glycerol-3-phosphate dehydrogenase activity in rat liver while having no effect in the heart. Because of the low oral bioavailability of PA 22c, a series of prodrugs was synthesized and screened for oral efficacy in the CFR assay. The liver-activated cyclic 1-(3-chlorophenyl)-1,3-propanyl prodrug (MB07811) showed potent lipid lowering activity in the CFR (ED50 0.4 mg/kg, po) and good oral bioavailability (40%, rat) and was selected for development for the treatment of hypercholesterolemia.

  DOI：

  10.1021/jm800824d
• 作为产物：
  描述：

  甲磺酸,三氟-,(diethoxyphosphinyl)甲基酯 、 3,5-dibromo-4-(4'-hydroxy-3'-isopropylphenoxy)phenol 在 caesium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 4-[2,6-Dibromo-4-(diethoxyphosphorylmethoxy)phenoxy]-2-propan-2-ylphenol
  参考文献：
  名称：

  Synthesis and Biological Evaluation of a Series of Liver-Selective Phosphonic Acid Thyroid Hormone Receptor Agonists and Their Prodrugs

  摘要：

  Phosphonic acid (PA) thyroid hormone receptor (TR) agonists were synthesized to exploit the poor distribution of PA-based drugs to extrahepatic tissues and thereby to improve the therapeutic index. Nine PAs showed excellent TR binding affinities (TR beta(1), K-i < 10 nM), and most of them demonstrated significant cholesterol lowering effects in a cholesterol-fed rat (CFR) model. Unlike the corresponding carboxylic acid analogue and T-3, PA 22c demonstrated liver-selective effects by inducing maximal mitochondrial glycerol-3-phosphate dehydrogenase activity in rat liver while having no effect in the heart. Because of the low oral bioavailability of PA 22c, a series of prodrugs was synthesized and screened for oral efficacy in the CFR assay. The liver-activated cyclic 1-(3-chlorophenyl)-1,3-propanyl prodrug (MB07811) showed potent lipid lowering activity in the CFR (ED50 0.4 mg/kg, po) and good oral bioavailability (40%, rat) and was selected for development for the treatment of hypercholesterolemia.

  DOI：

  10.1021/jm800824d

文献信息

• Method of treating glycogen storage disease
  申请人：Viking Therapeutics, Inc.

  公开号：US11202789B2

  公开（公告）日：2021-12-21

  The present disclosure provides methods and compositions for the treatment of hepatic symptoms of glycogen storage diseases through the administration of thyroid hormone receptor agonists. The methods and compositions provided herein are useful in the treatment of hyperlipidemia, hypercholesterolemia, hepatic steatosis, cardiomegaly, hepatomegaly, hepatic fibrosis, and cirrhosis associated with glycogen storage diseases (GSD) and defects of glycogen metabolism. Said compounds may also be useful in the prevention of GSD-related hepatocellular adenoma and hepatocellular carcinoma.

  本公开提供了通过服用甲状腺激素受体激动剂治疗糖原贮积病的肝脏症状的方法和组合物。本文提供的方法和组合物可用于治疗与糖原贮积病（GSD）和糖原代谢缺陷相关的高脂血症、高胆固醇血症、肝脂肪变性、心脏肿大、肝肿大、肝纤维化和肝硬化。上述化合物还可用于预防与 GSD 相关的肝细胞腺瘤和肝细胞癌。
• METHOD OF TREATING GLYCOGEN STORAGE DISEASE
  申请人：Viking Therapeutics, Inc.

  公开号：US20190343850A1

  公开（公告）日：2019-11-14

  The present disclosure provides methods and compositions for the treatment of hepatic symptoms of glycogen storage diseases through the administration of thyroid hormone receptor agonists. The methods and compositions provided herein are useful in the treatment of hyperlipidemia, hypercholesterolemia, hepatic steatosis, cardiomegaly, hepatomegaly, hepatic fibrosis, and cirrhosis associated with glycogen storage diseases (GSD) and defects of glycogen metabolism. Said compounds may also be useful in the prevention of GSD-related hepatocellular adenoma and hepatocellular carcinoma.
• Synthesis and Biological Evaluation of a Series of Liver-Selective Phosphonic Acid Thyroid Hormone Receptor Agonists and Their Prodrugs
  作者：Serge H. Boyer、Hongjian Jiang、Jason D. Jacintho、Mali Venkat Reddy、Haiqing Li、Wenyu Li、Jennifer L. Godwin、William G. Schulz、Edward E. Cable、Jinzhao Hou、Rongrong Wu、James M. Fujitaki、Scott J. Hecker、Mark D. Erion

  DOI：10.1021/jm800824d

  日期：2008.11.27

  Phosphonic acid (PA) thyroid hormone receptor (TR) agonists were synthesized to exploit the poor distribution of PA-based drugs to extrahepatic tissues and thereby to improve the therapeutic index. Nine PAs showed excellent TR binding affinities (TR beta(1), K-i < 10 nM), and most of them demonstrated significant cholesterol lowering effects in a cholesterol-fed rat (CFR) model. Unlike the corresponding carboxylic acid analogue and T-3, PA 22c demonstrated liver-selective effects by inducing maximal mitochondrial glycerol-3-phosphate dehydrogenase activity in rat liver while having no effect in the heart. Because of the low oral bioavailability of PA 22c, a series of prodrugs was synthesized and screened for oral efficacy in the CFR assay. The liver-activated cyclic 1-(3-chlorophenyl)-1,3-propanyl prodrug (MB07811) showed potent lipid lowering activity in the CFR (ED50 0.4 mg/kg, po) and good oral bioavailability (40%, rat) and was selected for development for the treatment of hypercholesterolemia.