(3-(2,5-dichlorophenoxy)pyrazin-2-yl)(3,4-dihydroquinolin-1(2H)-yl)methanone | 1415407-08-7

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (3-(2,5-dichlorophenoxy)pyrazin-2-yl)(3,4-dihydroquinolin-1(2H)-yl)methanone
• 英文别名: [3-(2,5-dichlorophenoxy)pyrazin-2-yl]-(3,4-dihydro-2H-quinolin-1-yl)methanone
• CAS: 1415407-08-7
• 化学式: C₂₀H₁₅Cl₂N₃O₂
• 分子量: 400.264
• InChiKey: BVJGNHRLBSXPEY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  27
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  55.3
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  甲基-3-溴吡嗪-2-羧酸甲酯 在 copper(l) iodide 、 草酰氯 、 水 、 铜 、 potassium carbonate 、 三乙胺 、 sodium hydroxide 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 生成 (3-(2,5-dichlorophenoxy)pyrazin-2-yl)(3,4-dihydroquinolin-1(2H)-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

文献信息

• Design, synthesis and evaluation of 3-phenoxypyrazine-2-carboxamide derivatives as potent TGR5 agonists
  作者：Shizhen Zhao、Le Wang、Jie Wang、Chenwei Wang、Shaowei Zheng、Yajie Fu、Yunfu Li、Wei-Dong Chen、Ruifang Hou、Dongbin Yang、Yan-Dong Wang

  DOI：10.1039/d1ra08867j

  日期：——

  TGR5 is emerging as an important and promising target for the treatment of non-alcoholic steatohepatitis, type 2 diabetes mellitus (T2DM), and obesity. A series of novel 3-phenoxypyrazine-2-carboxamide derivatives were designed, synthesized and evaluated in vitro and in vivo. The most potent compounds 18g and 18k exhibited excellent hTGR5 agonist activity, which was superior to those of the reference

  TGR5 正在成为治疗非酒精性脂肪性肝炎、2 型糖尿病 (T2DM) 和肥胖症的重要且有希望的靶点。设计、合成并在体外和体内评估了一系列新型 3-苯氧基吡嗪-2-甲酰胺衍生物。最有效的化合物18g和18k表现出优异的 hTGR5 激动剂活性，优于参考药物 INT-777。此外，化合物18k可显着降低 C57 BL/6 小鼠的血糖水平，并刺激 NCI-H716 细胞和 C57 BL/6 小鼠的 GLP-1 分泌。
• 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.