(3R)-3-(5-phenyl-1H-imidazol-2-yl)-1-(thian-4-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole | 1360889-95-7

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 哈马拉生物碱
• 英文名称: (3R)-3-(5-phenyl-1H-imidazol-2-yl)-1-(thian-4-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole
• CAS: 1360889-95-7
• 化学式: C₂₅H₂₆N₄S
• 分子量: 414.574
• InChiKey: LRRPBUZCJGWMNN-FKHAVUOCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  30
• 可旋转键数：
  3
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  81.8
• 氢给体数：
  3
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  BOC-D-色氨酸 在 盐酸 、 ammonium acetate 、 caesium carbonate 、 三氟乙酸 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 3.0h， 生成 (3R)-3-(5-phenyl-1H-imidazol-2-yl)-1-(thian-4-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole
  参考文献：
  名称：

  Stimulation of Glucose-Dependent Insulin Secretion by a Potent, Selective sst₃ Antagonist

  摘要：

  This letter provides the first pharmacological proof of principle that the sst(3) receptor mediates glucose-stimulated insulin secretion (GSIS) from pancreatic beta-cells. To enable these studies, we identified the selective sst3 antagonist (1R,3R)-3-(5-phenyl-1H-imidazol-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-2,,3,4,9-tetrahydro-1H-beta-carboline (5a), with improved ion channel selectivity and mouse pharmacokinetic properties as compared to previously described tetrahydro-beta-carboline imidazole sst3 antagonists. We demonstrated that compound 5a enhances GSIS in pancreatic beta-cells and blocks glucose excursion induced by dextrose challenge in ipGTT and OGTT models in mice. Finally, we provided strong evidence that these effects are mechanism-based in an ipGTT study, showing reduction of glucose excursion in wild-type but not sst(3) knockout mice. Thus, we have shown that antagonism of sst(3) represents a new mechanism with potential in treating type 2 diabetes mellitus.

  DOI：

  10.1021/ml200272z

文献信息

• Stimulation of Glucose-Dependent Insulin Secretion by a Potent, Selective sst₃ Antagonist
  作者：Alexander Pasternak、Zhe Feng、Reynalda de Jesus、Zhixiong Ye、Shuwen He、Peter Dobbelaar、Scott A. Bradley、Gary G. Chicchi、Kwei-Lan Tsao、Dorina Trusca、George J. Eiermann、Cai Li、Yue Feng、Margaret Wu、Qing Shao、Bei B. Zhang、Ravi Nargund、Sander G. Mills、Andrew D. Howard、Lihu Yang、Yun-Ping Zhou

  DOI：10.1021/ml200272z

  日期：2012.4.12

  This letter provides the first pharmacological proof of principle that the sst(3) receptor mediates glucose-stimulated insulin secretion (GSIS) from pancreatic beta-cells. To enable these studies, we identified the selective sst3 antagonist (1R,3R)-3-(5-phenyl-1H-imidazol-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-2,,3,4,9-tetrahydro-1H-beta-carboline (5a), with improved ion channel selectivity and mouse pharmacokinetic properties as compared to previously described tetrahydro-beta-carboline imidazole sst3 antagonists. We demonstrated that compound 5a enhances GSIS in pancreatic beta-cells and blocks glucose excursion induced by dextrose challenge in ipGTT and OGTT models in mice. Finally, we provided strong evidence that these effects are mechanism-based in an ipGTT study, showing reduction of glucose excursion in wild-type but not sst(3) knockout mice. Thus, we have shown that antagonism of sst(3) represents a new mechanism with potential in treating type 2 diabetes mellitus.