(S)-methyl 4'-(6-(2-((4-cyanophenylethyl)carbamoyl)azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-[1,1'-biphenyl]-4-carboxylate | 1595145-35-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: (S)-methyl 4'-(6-(2-((4-cyanophenylethyl)carbamoyl)azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-[1,1'-biphenyl]-4-carboxylate
• CAS: 1595145-35-9
• 化学式: C₃₂H₂₆F₃N₅O₃
• 分子量: 585.585
• InChiKey: FSQNAMFXQFPCGQ-MHZLTWQESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.43
• 重原子数：
  43.0
• 可旋转键数：
  8.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  108.21
• 氢给体数：
  1.0
• 氢受体数：
  7.0

反应信息

• 作为反应物：
  描述：

  (S)-methyl 4'-(6-(2-((4-cyanophenylethyl)carbamoyl)azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-[1,1'-biphenyl]-4-carboxylate 在 lithium hydroxide 、 柠檬酸 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 为溶剂， 反应 1.5h， 以93%的产率得到4-(4-{6-[(2S)-2-{[2-(4-cyanophenyl)ethyl]carbamoyl}azetidin-1-yl]-2-(trifluoromethyl)pyrimidin-4-yl}phenyl)benzoic acid
  参考文献：
  名称：

  Discovery of Trifluoromethyl(pyrimidin-2-yl)azetidine-2-carboxamides as Potent, Orally Bioavailable TGR5 (GPBAR1) Agonists: Structure–Activity Relationships, Lead Optimization, and Chronic In Vivo Efficacy

  摘要：

  Activation of the G-protein coupled receptor (GPCR) Takeda G-protein receptor 5 (TGR5), also known as G-protein bile acid receptor 1 (GPBAR1), has been shown to play a key role in pathways associated with diabetes, metabolic syndrome, and autoimmune disease. Nipecotamide 5 was identified as an attractive starting point after a high-throughput screen (HTS) for receptor agonists. A comprehensive hit-to-lead effort culminated in the discovery of 45h as a potent, selective, and bioavailable TGR5 agonist to test in preclinical metabolic disease models. In genetically obese mice (ob/ob), 45h was as effective as a dipeptidyl peptidase-4 (DPP-4) inhibitor at reducing peak glucose levels in an acute oral glucose tolerance test (OGTT), but this effect was lost upon chronic dosing.

  DOI：

  10.1021/jm401731q
• 作为产物：
  描述：

  4’-溴[1,1’-联苯]-4-甲酸甲酯 在 2-双环己基膦-2',6'-二甲氧基联苯 、 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 potassium phosphate 、 tris-(dibenzylideneacetone)dipalladium(0) 、 potassium acetate 作用下， 以 1,4-二氧六环 、 水 为溶剂， 反应 21.0h， 生成 (S)-methyl 4'-(6-(2-((4-cyanophenylethyl)carbamoyl)azetidin-1-yl)-2-(trifluoromethyl)pyrimidin-4-yl)-[1,1'-biphenyl]-4-carboxylate
  参考文献：
  名称：

  Discovery of Trifluoromethyl(pyrimidin-2-yl)azetidine-2-carboxamides as Potent, Orally Bioavailable TGR5 (GPBAR1) Agonists: Structure–Activity Relationships, Lead Optimization, and Chronic In Vivo Efficacy

  摘要：

  Activation of the G-protein coupled receptor (GPCR) Takeda G-protein receptor 5 (TGR5), also known as G-protein bile acid receptor 1 (GPBAR1), has been shown to play a key role in pathways associated with diabetes, metabolic syndrome, and autoimmune disease. Nipecotamide 5 was identified as an attractive starting point after a high-throughput screen (HTS) for receptor agonists. A comprehensive hit-to-lead effort culminated in the discovery of 45h as a potent, selective, and bioavailable TGR5 agonist to test in preclinical metabolic disease models. In genetically obese mice (ob/ob), 45h was as effective as a dipeptidyl peptidase-4 (DPP-4) inhibitor at reducing peak glucose levels in an acute oral glucose tolerance test (OGTT), but this effect was lost upon chronic dosing.

  DOI：

  10.1021/jm401731q