methyl 4-[(3R)-3-(5-phenyl-1H-imidazol-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]piperidine-1-carboxylate | 1104604-93-4

• 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: methyl 4-[(3R)-3-(5-phenyl-1H-imidazol-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]piperidine-1-carboxylate
• CAS: 1104604-93-4
• 化学式: C₂₇H₂₉N₅O₂
• 分子量: 455.56
• InChiKey: WLWPJGTZCVDLGP-LETIRJCYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  34
• 可旋转键数：
  4
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  86
• 氢给体数：
  3
• 氢受体数：
  4

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 methyl 4-[(3R)-3-(5-phenyl-1H-imidazol-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]piperidine-1-carboxylate
  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

• BETA CARBOLINE DERIVATIVES AS ANTIDIABETIC COMPOUNDS
  申请人：Dobbelaar Peter H.

  公开号：US20100184758A1

  公开（公告）日：2010-07-22

  Beta-carboline derivatives of structural formula I are selective antagonists of the somatostatin subtype receptor 3 (SSTR3) and are useful for the treatment of Type 2 diabetes mellitus and of conditions that are often associated with this disease, including hyperglycemia, insulin resistance, obesity, lipid disorders, and hypertension. The compounds are also useful for the treatment of depression and anxiety.

  结构式I的β-咔啉衍生物是生长抑素亚型受体3（SSTR3）的选择性拮抗剂，可用于治疗2型糖尿病以及通常与该疾病相关的病症，包括高血糖、胰岛素抵抗、肥胖、脂质异常和高血压。这些化合物还可用于治疗抑郁症和焦虑症。
• [EN] BETA CARBOLINE DERIVATIVES AS ANTIDIABETIC COMPOUNDS<br/>[FR] DÉRIVÉS DE BÊTA-CARBOLINE EN TANT QUE COMPOSÉS ANTIDIABÉTIQUES
  申请人：MERCK & CO INC

  公开号：WO2009011836A1

  公开（公告）日：2009-01-22

  Beta-carboline derivatives of structural formula I are selective antagonists of the somatostatin subtype receptor 3 (SSTR3) and are useful for the treatment of Type 2 diabetes mellitus and of conditions that are often associated with this disease, including hyperglycemia, insulin resistance, obesity, lipid disorders, and hypertension. The compounds are also useful for the treatment of depression and anxiety.
• 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.