2-(7-((3-fluorobenzyl)oxy)-4,8-dimethyl-2-oxo-2H-chromen-3-yl)acetic acid | 858752-73-5

• 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: 2-(7-((3-fluorobenzyl)oxy)-4,8-dimethyl-2-oxo-2H-chromen-3-yl)acetic acid
• 英文别名: {7-[(3-fluorobenzyl)oxy]-4,8-dimethyl-2-oxo-2H-chromen-3-yl}acetic acid；2-[7-[(3-fluorophenyl)methoxy]-4,8-dimethyl-2-oxochromen-3-yl]acetic acid
• CAS: 858752-73-5
• 化学式: C₂₀H₁₇FO₅
• mdl: MFCD03851238
• 分子量: 356.35
• InChiKey: KWGHOPKGQKLTEJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  26
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  72.8
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  乙酰丁二酸二甲酯 在 硫酸 、 水 、 potassium carbonate 、 sodium hydroxide 作用下， 以 甲醇 、 丙酮 为溶剂， 反应 26.0h， 生成 2-(7-((3-fluorobenzyl)oxy)-4,8-dimethyl-2-oxo-2H-chromen-3-yl)acetic acid
  参考文献：
  名称：

  4,8-Dimethylcoumarin Inhibitors of Intestinal Anion Exchanger slc26a3 (Downregulated in Adenoma) for Anti-Absorptive Therapy of Constipation

  摘要：

  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.

  DOI：

  10.1021/acs.jmedchem.9b01192

文献信息

• SLC26A3 INHIBITORS AND USE THEREOF
  申请人：THE REGENTS OF THE UNIVERSITY OF CALIFORNIA

  公开号：US20210363123A1

  公开（公告）日：2021-11-25

  Provided herein are inhibitors of SLC26A3, which is an anion (CV, HCO 3 , oxalate) exchanger expressed in intestinal epithelial cells. SLC26A3 inhibitors have potential utility for treatment of constipation including chronic idiopathic constipation (CIC), opioid-induced constipation (OIC), constipation-predominant irritable bowel syndrome (IBS-C), cystic fibrosis-associated constipation, meconium ileus, distal intestinal obstruction syndrome, calcium oxalate kidney stone disease, enteric hyperoxaluria and primary hyperoxalurias.