ethyl 4-(2,5-dichloro-4-bromophenoxy)nicotinate | 1415407-45-2

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: ethyl 4-(2,5-dichloro-4-bromophenoxy)nicotinate
• 英文别名: Ethyl 4-(4-bromo-2,5-dichlorophenoxy)pyridine-3-carboxylate；ethyl 4-(4-bromo-2,5-dichlorophenoxy)pyridine-3-carboxylate
• CAS: 1415407-45-2
• 化学式: C₁₄H₁₀BrCl₂NO₃
• 分子量: 391.048
• InChiKey: VDOLVGYGBGVCFF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  21
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  48.4
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  ethyl 4-(2,5-dichloro-4-bromophenoxy)nicotinate 在 草酰氯 、 水 、 三乙胺 、 sodium hydroxide 作用下， 以 1,4-二氧六环 、 二氯甲烷 为溶剂， 反应 7.0h， 生成 [4-(2,5-dichloro-4-bromophenoxy)pyridin-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)methanone
  参考文献：
  名称：

  Design, Synthesis, and Antidiabetic Activity of 4-Phenoxynicotinamide and 4-Phenoxypyrimidine-5-carboxamide Derivatives as Potent and Orally Efficacious TGR5 Agonists

  摘要：

  4-Phenoxynicotinamide and 4-phenoxypyrimidine-5-carboxamide derivatives as potent and orally efficacious TGR5 agonists are reported. Several 4-phenoxynicotinamide derivatives were found to activate human and mouse TGR5 (hTGR5 and mTGR5) with EC50 values in the low nanomolar range. Compound 23g, with an EC50 value of 0.72 nM on hTGR5 and an EC50 value of 6.2 nM on mTGR5, was selected for further in vivo efficacy studies. This compound exhibited a significant dose-dependent glucagon-like peptide-1 (GLP-1) secretion effect. A single oral dose of 23g (50 mg/kg) significantly reduced blood glucose levels in db/db mice and caused a 49% reduction in the area under the blood glucose curve (AUC)(0-120) (min) following an oral glucose tolerance test (OGTT) in imprinting control region (ICR) mice. However, 23g stimulated gallbladder filling, which might result in side effects to the gallbladder.

  DOI：

  10.1021/jm301071h
• 作为产物：
  描述：

  4-氯烟酰氯化物 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 3.0h， 生成 ethyl 4-(2,5-dichloro-4-bromophenoxy)nicotinate
  参考文献：
  名称：

  Design, Synthesis, and Antidiabetic Activity of 4-Phenoxynicotinamide and 4-Phenoxypyrimidine-5-carboxamide Derivatives as Potent and Orally Efficacious TGR5 Agonists

  摘要：

  4-Phenoxynicotinamide and 4-phenoxypyrimidine-5-carboxamide derivatives as potent and orally efficacious TGR5 agonists are reported. Several 4-phenoxynicotinamide derivatives were found to activate human and mouse TGR5 (hTGR5 and mTGR5) with EC50 values in the low nanomolar range. Compound 23g, with an EC50 value of 0.72 nM on hTGR5 and an EC50 value of 6.2 nM on mTGR5, was selected for further in vivo efficacy studies. This compound exhibited a significant dose-dependent glucagon-like peptide-1 (GLP-1) secretion effect. A single oral dose of 23g (50 mg/kg) significantly reduced blood glucose levels in db/db mice and caused a 49% reduction in the area under the blood glucose curve (AUC)(0-120) (min) following an oral glucose tolerance test (OGTT) in imprinting control region (ICR) mice. However, 23g stimulated gallbladder filling, which might result in side effects to the gallbladder.

  DOI：

  10.1021/jm301071h

文献信息

• Design, Synthesis, and Antidiabetic Activity of 4-Phenoxynicotinamide and 4-Phenoxypyrimidine-5-carboxamide Derivatives as Potent and Orally Efficacious TGR5 Agonists
  作者：Hongliang Duan、Mengmeng Ning、Xiaoyan Chen、Qingan Zou、Liming Zhang、Ying Feng、Lina Zhang、Ying Leng、Jianhua Shen

  DOI：10.1021/jm301071h

  日期：2012.12.13

  4-Phenoxynicotinamide and 4-phenoxypyrimidine-5-carboxamide derivatives as potent and orally efficacious TGR5 agonists are reported. Several 4-phenoxynicotinamide derivatives were found to activate human and mouse TGR5 (hTGR5 and mTGR5) with EC50 values in the low nanomolar range. Compound 23g, with an EC50 value of 0.72 nM on hTGR5 and an EC50 value of 6.2 nM on mTGR5, was selected for further in vivo efficacy studies. This compound exhibited a significant dose-dependent glucagon-like peptide-1 (GLP-1) secretion effect. A single oral dose of 23g (50 mg/kg) significantly reduced blood glucose levels in db/db mice and caused a 49% reduction in the area under the blood glucose curve (AUC)(0-120) (min) following an oral glucose tolerance test (OGTT) in imprinting control region (ICR) mice. However, 23g stimulated gallbladder filling, which might result in side effects to the gallbladder.
• Discovery of Intestinal Targeted TGR5 Agonists for the Treatment of Type 2 Diabetes
  作者：Hongliang Duan、Mengmeng Ning、Qingan Zou、Yangliang Ye、Ying Feng、Lina Zhang、Ying Leng、Jianhua Shen

  DOI：10.1021/jm500829b

  日期：2015.4.23

  Activation of TGR5 stimulates intestinal glucagon-like peptide-1 (GLP-1) release, but activation of the receptors in gallbladder and heart has been shown to cause severe on-target side effects. A series of low-absorbed TGR5 agonists was prepared by modifying compound 2 with polar functional groups to limit systemic exposure and specifically activate TGR5 in the intestine. Compound 15c, with a molecular weight of 1401, a PSA value of 223 angstrom(2), and low permeability on Caco-2 cells, exhibited satisfactory potency both in vitro and in vivo. Low levels of 15c were detected in blood, bile, and gallbladder tissue, and gallbladder-related side effects were substantially decreased compared to the absorbed small-molecule TGR5 agonist 2.