methyl 2-(4,8-dimethyl-2-oxo-7-((3-(trifluoromethyl)benzyl)oxy)-2H-chromen-3-yl)acetate

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 香豆素及其衍生物
• 英文名称: methyl 2-(4,8-dimethyl-2-oxo-7-((3-(trifluoromethyl)benzyl)oxy)-2H-chromen-3-yl)acetate
• 英文别名: methyl (4,8-dimethyl-2-oxo-7-{[3-(trifluoromethyl)benzyl]oxy}-2H-chromen-3-yl)acetate；methyl 2-[4,8-dimethyl-2-oxo-7-[[3-(trifluoromethyl)phenyl]methoxy]chromen-3-yl]acetate
• 化学式: C₂₂H₁₉F₃O₅
• mdl: MFCD03721630
• 分子量: 420.385
• InChiKey: RZLONORSWULDMA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  30
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  61.8
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  methyl 2-(4,8-dimethyl-2-oxo-7-((3-(trifluoromethyl)benzyl)oxy)-2H-chromen-3-yl)acetate 在 sodium hydroxide 作用下， 以 甲醇 为溶剂， 以81 %的产率得到2-(4,8-dimethyl-2-oxo-7-((3-(trifluoromethyl)benzyl)oxy)-2H-chromen-3-yl)acetic acid
  参考文献：
  名称：

  Substituted 4-methylcoumarin inhibitors of SLC26A3 (DRA) for treatment of constipation and hyperoxaluria

  摘要：

  Substituted 4-methylcoumarins were found to be active against SLC26A3 (DRA) using in vitro and in vivo assays.

  DOI：

  10.1039/d3md00644a
• 作为产物：
  描述：

  乙酰丁二酸二甲酯 在 硫酸 、 potassium carbonate 作用下， 以 丙酮 为溶剂， 反应 48.0h， 生成 methyl 2-(4,8-dimethyl-2-oxo-7-((3-(trifluoromethyl)benzyl)oxy)-2H-chromen-3-yl)acetate
  参考文献：
  名称：

  Substituted 4-methylcoumarin inhibitors of SLC26A3 (DRA) for treatment of constipation and hyperoxaluria

  摘要：

  Substituted 4-methylcoumarins were found to be active against SLC26A3 (DRA) using in vitro and in vivo assays.

  DOI：

  10.1039/d3md00644a

文献信息

• 4,8-Dimethylcoumarin Inhibitors of Intestinal Anion Exchanger slc26a3 (Downregulated in Adenoma) for Anti-Absorptive Therapy of Constipation
  作者：Sujin Lee、Onur Cil、Peter M. Haggie、Alan S. Verkman

  DOI：10.1021/acs.jmedchem.9b01192

  日期：2019.9.12

  The chloride/bicarbonate exchanger SLC26A3 (downregulated in adenoma) is expressed mainly in colonic epithelium, where it dehydrates the stool by facilitating the final step of chloride and fluid absorption. SLC26A3 inhibition has predicted efficacy in various types of constipation including that associated with cystic fibrosis. We previously identified, by high-throughput screening, 4,8-dimethylcoumarin inhibitors of murine slc26a3 with IC50 down to similar to 150 nM. Here, we synthesized a focused library of forty-three 4,8-dimethylcoumarin analogues. Structure-activity studies revealed the requirement of 4,8-dimethylcoumarin-3-acetic acid for activity. The most potent inhibitors were produced by replacements at C7, including 3-iodo- (4az) and 3-trifluoromethyl- (4be), with IC50 of 40 and 25 nM, respectively. Pharmacokinetics in mice showed predicted therapeutic concentrations of 4az for >72 h following a single 10 mg/kg oral dose. 4az at 10 mg/kg fully normalized stool water content in a loperamide-induced mouse model of constipation. The favorable inhibition potency, selectivity within the SLC26 family, and pharmacological properties of 4az support its further preclinical development.