(2-benzylpiperidin-1-yl)(4-(1-hydroxy-1-phenylethyl)-2H-1,2,3-triazol-2-yl)methanone

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: (2-benzylpiperidin-1-yl)(4-(1-hydroxy-1-phenylethyl)-2H-1,2,3-triazol-2-yl)methanone
• 英文别名: (2-Benzylpiperidin-1-yl)-[4-(1-hydroxy-1-phenylethyl)triazol-2-yl]methanone；(2-benzylpiperidin-1-yl)-[4-(1-hydroxy-1-phenylethyl)triazol-2-yl]methanone
• 化学式: C₂₃H₂₆N₄O₂
• 分子量: 390.485
• InChiKey: ARWPUXNOXVMUTI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  71.2
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  2-苄基吡啶 在 盐酸 、 platinum(IV) oxide 、 氢气 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 乙醇 、 水 为溶剂， 反应 2.5h， 生成 (2-benzylpiperidin-1-yl)(4-(1-hydroxy-1-phenylethyl)-2H-1,2,3-triazol-2-yl)methanone
  参考文献：
  名称：

  Triazole Ureas Act as Diacylglycerol Lipase Inhibitors and Prevent Fasting-Induced Refeeding

  摘要：

  Triazole ureas constitute a versatile class of irreversible inhibitors that target serine hydrolases in both cells and animal models. We have previously reported that triazole ureas can act as selective and CNS-active inhibitors for diacylglycerol lipases (DAGLs), enzymes responsible for the biosynthesis of 2-arachidonoylglycerol (2 -AG) that activates cannabinoid CB1 receptor. Here, we report the enantio- and diastereoselective synthesis and structure-activity relationship studies. We found that 2,4 -substituted triazole ureas with a biphenylmethanol group provided the most optimal scaffold. Introduction of a chiral ether substituent on the 5 -position of the piperidine ring provided ultrapotent inhibitor 38 (DH376) with picomolar activity. Compound 38 temporarily reduces fasting -induced refeeding of mice, thereby emulating the effect of cannabinoid' CB1-receptor inverse agonists. This was mirrored by 39 (DO34) but also by the negative control compound 40 (DO53) (which does not inhibit DAGL), which indicates the triazole ureas may affect the energy balance in mice through multiple molecular targets.

  DOI：

  10.1021/acs.jmedchem.6b01482

文献信息

• Triazole Ureas Act as Diacylglycerol Lipase Inhibitors and Prevent Fasting-Induced Refeeding
  作者：Hui Deng、Sander Kooijman、Adrianus M. C. H. van den Nieuwendijk、Daisuke Ogasawara、Tom van der Wel、Floris van Dalen、Marc P. Baggelaar、Freek J. Janssen、Richard J. B. H. N. van den Berg、Hans den Dulk、Benjamin F. Cravatt、Herman S. Overkleeft、Patrick C. N. Rensen、Mario van der Stelt

  DOI：10.1021/acs.jmedchem.6b01482

  日期：2017.1.12

  Triazole ureas constitute a versatile class of irreversible inhibitors that target serine hydrolases in both cells and animal models. We have previously reported that triazole ureas can act as selective and CNS-active inhibitors for diacylglycerol lipases (DAGLs), enzymes responsible for the biosynthesis of 2-arachidonoylglycerol (2 -AG) that activates cannabinoid CB1 receptor. Here, we report the enantio- and diastereoselective synthesis and structure-activity relationship studies. We found that 2,4 -substituted triazole ureas with a biphenylmethanol group provided the most optimal scaffold. Introduction of a chiral ether substituent on the 5 -position of the piperidine ring provided ultrapotent inhibitor 38 (DH376) with picomolar activity. Compound 38 temporarily reduces fasting -induced refeeding of mice, thereby emulating the effect of cannabinoid' CB1-receptor inverse agonists. This was mirrored by 39 (DO34) but also by the negative control compound 40 (DO53) (which does not inhibit DAGL), which indicates the triazole ureas may affect the energy balance in mice through multiple molecular targets.