ethyl 3-(3-(2,5-dichloro-4-((3-(4-cyclopropyl-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)pyridin-4-yl)oxy)phenyl)propanamido)propanoate

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: ethyl 3-(3-(2,5-dichloro-4-((3-(4-cyclopropyl-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)pyridin-4-yl)oxy)phenyl)propanamido)propanoate
• 英文别名: Ethyl 3-[3-[2,5-dichloro-4-[3-(4-cyclopropyl-2,3-dihydroquinoxaline-1-carbonyl)pyridin-4-yl]oxyphenyl]propanoylamino]propanoate；ethyl 3-[3-[2,5-dichloro-4-[3-(4-cyclopropyl-2,3-dihydroquinoxaline-1-carbonyl)pyridin-4-yl]oxyphenyl]propanoylamino]propanoate
• 化学式: C₃₁H₃₂Cl₂N₄O₅
• 分子量: 611.525
• InChiKey: IIZAIMAUDSHALP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  42
• 可旋转键数：
  12
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  101
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  ethyl 3-(3-(2,5-dichloro-4-((3-(4-cyclopropyl-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)pyridin-4-yl)oxy)phenyl)propanamido)propanoate 在 水 、 sodium hydroxide 作用下， 以 1,4-二氧六环 为溶剂， 反应 2.0h， 以85%的产率得到3-(3-(2,5-dichloro-4-((3-(4-cyclopropyl-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)pyridin-4-yl)oxy)phenyl)propanamido)propanoic acid
  参考文献：
  名称：

  Discovery of Intestinal Targeted TGR5 Agonists for the Treatment of Type 2 Diabetes

  摘要：

  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.

  DOI：

  10.1021/jm500829b
• 作为产物：
  描述：

  [4-(2,5-dichloro-4-bromophenoxy)pyridin-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)methanone 在 甲醇 、 sodium tetrahydroborate 、 水 、 palladium diacetate 、 三乙胺 、 三(邻甲基苯基)磷 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 、 copper(l) chloride 、 sodium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 、 乙腈 为溶剂， 反应 6.0h， 生成 ethyl 3-(3-(2,5-dichloro-4-((3-(4-cyclopropyl-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)pyridin-4-yl)oxy)phenyl)propanamido)propanoate
  参考文献：
  名称：

  Discovery of Intestinal Targeted TGR5 Agonists for the Treatment of Type 2 Diabetes

  摘要：

  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.

  DOI：

  10.1021/jm500829b

文献信息

• 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.