SSTR5拮抗剂2TFA | 1254733-98-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 中文名称: SSTR5拮抗剂2TFA
• 英文名称: 4-{8-[(2,6-diethoxy-4'-fluorobiphenyl-4-yl)methyl]-3-oxo-2,8-diazaspiro[4.5]dec-2-yl}benzoic acid trifluoroacetic acid
• 英文别名: SSTR5 antagonist 2 TFA；4-[8-[[3,5-diethoxy-4-(4-fluorophenyl)phenyl]methyl]-3-oxo-2,8-diazaspiro[4.5]decan-2-yl]benzoic acid;2,2,2-trifluoroacetic acid
• CAS: 1254733-98-6
• 化学式: C₂HF₃O₂*C₃₂H₃₅FN₂O₅
• 分子量: 660.663
• InChiKey: VFUWYNPQDXMVOJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.64
• 重原子数：
  47
• 可旋转键数：
  9
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  117
• 氢给体数：
  2
• 氢受体数：
  12

制备方法与用途

生物活性

SSTR5 抗拮抗剂 2 TFA (化合物 10) 是一种强效且具有口服活性的生长激素抑制激素受体亚型 5（SSTR5）的选择性拮抗剂，有潜力用于 2 型糖尿病的研究。

靶点

• SSTR5

体内研究

• 在小鼠中，10 mg/kg 口服剂量的 SSTR5 拮抗剂 2 可增加总水平和活性循环肠促胰岛素激素 GLP1 的水平。
• 此药物还增加了胰腺胰岛素分泌以及总水平和活性 GLP1 的释放，并且与 DPP4 抑制剂联用时显示出协同效应。

研究结果

• 动物模型: 无低血糖风险的啮齿类糖尿病模型
• 剂量: 10 mg/kg
• 给药方式: 口服
• 结果: 增加了总水平和活性循环肠促胰岛素激素 GLP1 的水平

反应信息

• 作为反应物：
  描述：

  SSTR5拮抗剂2TFA 在 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 氨 作用下， 以 四氢呋喃 为溶剂， 反应 0.27h， 生成 4-[8-[[3,5-Diethoxy-4-(4-fluorophenyl)phenyl]methyl]-3-oxo-2,8-diazaspiro[4.5]decan-2-yl]benzamide
  参考文献：
  名称：

  [EN] SUBSTITUTED SPIROCYCLIC AMINES USEFUL AS ANTIDIABETIC COMPOUNDS
  [FR] AMINES SPIROCYCLIQUES SUBSTITUÉES UTILES EN TANT QUE COMPOSÉS ANTIDIABÉTIQUES

  摘要：

  结构式I的螺环胺是生长抑素亚型受体5（SSTR5）的选择性拮抗剂，可用于治疗、控制或预防对SSTR5拮抗敏感的疾病，如2型糖尿病、胰岛素抵抗、脂质紊乱、肥胖、动脉粥样硬化、代谢综合征、抑郁症和焦虑症。

  公开号：

  WO2010129729A1
• 作为产物：
  描述：

  4-溴-3,5-二羟基苯甲酸 在 tris-(dibenzylideneacetone)dipalladium(0) 、 lithium aluminium tetrahydride 、 potassium carbonate 、 甲基磺酰氯 、 三乙胺 、 cesium fluoride 、 lithium hydroxide 、 tri tert-butylphosphoniumtetrafluoroborate 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 58.0h， 生成 SSTR5拮抗剂2TFA
  参考文献：
  名称：

  Discovery and Pharmacology of a Novel Somatostatin Subtype 5 (SSTR5) Antagonist: Synergy with DPP-4 Inhibition

  摘要：

  We report new SSTR5 antagonists with enhanced potency, subtype selectivity, and minimal off-target activities as compared to previously reported compounds. Starting from the reported SSTR5 antagonist 1, we systematically surveyed changes in the central core and head piece while maintaining the diphenyl tail group constant. From this study the azaspirodecanone 10 emerged as a new highly potent and selective SSTR5 antagonist. Compound 10 lowered glucose excursion by 94% in an oral glucose tolerance test (OGTT) in mice following a 3 mg/kg oral dose. The compound increased both total and active circulating incretin hormone GLP-1 levels in mice at a dose of 10 mg/kg. A synergistic effect was also demonstrated when compound 10 was coadministered with a DPP-4 inhibitor, substantially increasing circulating active GLP-1[7-36] amide and insulin in response to a glucose challenge.

  DOI：

  10.1021/acsmedchemlett.8b00305

文献信息

• Discovery and Pharmacology of a Novel Somatostatin Subtype 5 (SSTR5) Antagonist: Synergy with DPP-4 Inhibition
  作者：Weiguo Liu、Pengcheng P. Shao、Gui-Bai Liang、John Bawiec、Jiafang He、Susan D. Aster、Margaret Wu、Garry Chicchi、John Wang、Kwei-Lan Tsao、Jin Shang、Gino Salituro、Yun-Ping Zhou、Cai Li、Taro E. Akiyama、Daniel E. Metzger、Beth Ann Murphy、Andrew D. Howard、Ann E. Weber、Joseph L. Duffy

  DOI：10.1021/acsmedchemlett.8b00305

  日期：2018.11.8

  We report new SSTR5 antagonists with enhanced potency, subtype selectivity, and minimal off-target activities as compared to previously reported compounds. Starting from the reported SSTR5 antagonist 1, we systematically surveyed changes in the central core and head piece while maintaining the diphenyl tail group constant. From this study the azaspirodecanone 10 emerged as a new highly potent and selective SSTR5 antagonist. Compound 10 lowered glucose excursion by 94% in an oral glucose tolerance test (OGTT) in mice following a 3 mg/kg oral dose. The compound increased both total and active circulating incretin hormone GLP-1 levels in mice at a dose of 10 mg/kg. A synergistic effect was also demonstrated when compound 10 was coadministered with a DPP-4 inhibitor, substantially increasing circulating active GLP-1[7-36] amide and insulin in response to a glucose challenge.
• [EN] SUBSTITUTED SPIROCYCLIC AMINES USEFUL AS ANTIDIABETIC COMPOUNDS<br/>[FR] AMINES SPIROCYCLIQUES SUBSTITUÉES UTILES EN TANT QUE COMPOSÉS ANTIDIABÉTIQUES
  申请人：MERCK SHARP & DOHME

  公开号：WO2010129729A1

  公开（公告）日：2010-11-11

  Substituted spirocyclic amines of structural formula I are selective antagonists of the somatostatin subtype receptor 5 (SSTR5) and are useful for the treatment, control or prevention of disorders responsive to antagonism of SSTR5, such as Type 2 diabetes, insulin resistance, lipid disorders, obesity, atherosclerosis, metabolic syndrome, depression, and anxiety.

  结构式I的螺环胺是生长抑素亚型受体5（SSTR5）的选择性拮抗剂，可用于治疗、控制或预防对SSTR5拮抗敏感的疾病，如2型糖尿病、胰岛素抵抗、脂质紊乱、肥胖、动脉粥样硬化、代谢综合征、抑郁症和焦虑症。