5-((2',6'-dimethylbiphenyl-3-yl)methoxy)thieno[3,2-b]thiophene-2-carboxylic acid

• 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: 5-((2',6'-dimethylbiphenyl-3-yl)methoxy)thieno[3,2-b]thiophene-2-carboxylic acid
• 英文别名: 5-[[3-(2,6-Dimethylphenyl)phenyl]methoxy]thieno[3,2-b]thiophene-2-carboxylic acid；5-[[3-(2,6-dimethylphenyl)phenyl]methoxy]thieno[3,2-b]thiophene-2-carboxylic acid
• 化学式: C₂₂H₁₈O₃S₂
• 分子量: 394.515
• InChiKey: BZFBGVPVNKOHDI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.7
• 重原子数：
  27
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  103
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  噻吩并[3,2-b]噻吩 在 sodium chlorite 、 copper(l) iodide 、 sodium dihydrogenphosphate dihydrate 、 2-甲基-2-丁烯 、 3,4,7,8-四甲基-1,10-菲罗啉 、 碘 、 1-羟基苯并三唑 、 caesium carbonate 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 、 [双(三氟乙酰氧基)碘]苯 、 sodium hydroxide 、 三氯氧磷 作用下， 以 四氢呋喃 、 甲醇 、 四氯化碳 、 二氯甲烷 、 水 、 1,2-二氯乙烷 、 甲苯 、 叔丁醇 为溶剂， 反应 48.5h， 生成 5-((2',6'-dimethylbiphenyl-3-yl)methoxy)thieno[3,2-b]thiophene-2-carboxylic acid
  参考文献：
  名称：

  Discovery of Potent and Orally Bioavailable GPR40 Full Agonists Bearing Thiophen-2-ylpropanoic Acid Scaffold

  摘要：

  The free fatty acid receptor GPR40 is predominantly expressed in pancreatic beta-cells and enhances insulin secretion in a glucose dependent manner. Therefore, GPR40 agonists are possible novel insulin secretagogues with reduced or no risk of hypoglycemia for the treatment of type 2 diabetes mellitus (T2DM). Chemically and structurally diverse GPR40 agonists with high safety are pursued for the clinical development of GPR40-based pharmacotherapeutics. Herein we report our design and discovery of a new chemotype of GPR40 agonists free of the typical phenylpropanoic acid scaffold. The thiophen-2-ylpropanoic acid containing GPR40 modulators functioned as full agonists with high-efficacy response (E-max) and reduced lipophilicity. Significantly, the lead compound in this series, (R)-7k, exhibited more potent in vitro glucose-stimulated insulin secretion and in vivo glucose-lowering effects (10 mg/kg, po) than the GPR40 partial agonist TAK-875, which was once in phase III clinical trials, and high selectivity over the relevant receptors GPR120 and PPAR gamma.

  DOI：

  10.1021/acs.jmedchem.6b01357

文献信息

• Discovery of Potent and Orally Bioavailable GPR40 Full Agonists Bearing Thiophen-2-ylpropanoic Acid Scaffold
  作者：He Li、Qi Huang、Cheng Chen、Bin Xu、He-Yao Wang、Ya-Qiu Long

  DOI：10.1021/acs.jmedchem.6b01357

  日期：2017.4.13

  The free fatty acid receptor GPR40 is predominantly expressed in pancreatic beta-cells and enhances insulin secretion in a glucose dependent manner. Therefore, GPR40 agonists are possible novel insulin secretagogues with reduced or no risk of hypoglycemia for the treatment of type 2 diabetes mellitus (T2DM). Chemically and structurally diverse GPR40 agonists with high safety are pursued for the clinical development of GPR40-based pharmacotherapeutics. Herein we report our design and discovery of a new chemotype of GPR40 agonists free of the typical phenylpropanoic acid scaffold. The thiophen-2-ylpropanoic acid containing GPR40 modulators functioned as full agonists with high-efficacy response (E-max) and reduced lipophilicity. Significantly, the lead compound in this series, (R)-7k, exhibited more potent in vitro glucose-stimulated insulin secretion and in vivo glucose-lowering effects (10 mg/kg, po) than the GPR40 partial agonist TAK-875, which was once in phase III clinical trials, and high selectivity over the relevant receptors GPR120 and PPAR gamma.