O-7460 | 1572051-31-0

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: O-7460
• 英文别名: 1-((fluoro(methyl)phosphoryl)oxy)-3-isopropoxypropan-2-yl oleate；[1-[Fluoro(methyl)phosphoryl]oxy-3-propan-2-yloxypropan-2-yl] (Z)-octadec-9-enoate；[1-[fluoro(methyl)phosphoryl]oxy-3-propan-2-yloxypropan-2-yl] (Z)-octadec-9-enoate
• CAS: 1572051-31-0
• 化学式: C₂₅H₄₈FO₅P
• 分子量: 478.625
• InChiKey: ZLEFMXNNQCABDB-SEYXRHQNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  8.1
• 重原子数：
  32
• 可旋转键数：
  23
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.88
• 拓扑面积：
  61.8
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  1-chloro-3-isopropoxypropan-2-yl oleate 在 三甲基溴硅烷 、 二甲氨基三氟化硫 、 sodium iodide 作用下， 以 二氯甲烷 为溶剂， 反应 51.5h， 生成 O-7460
  参考文献：
  名称：

  A novel fluorophosphonate inhibitor of the biosynthesis of the endocannabinoid 2-arachidonoylglycerol with potential anti-obesity effects

  摘要：

  Background and PurposeThe development of potent and selective inhibitors of the biosynthesis of the endocannabinoid 2‐arachidonoylglycerol (2‐AG) via DAG lipases (DAGL) α and β is just starting to be considered as a novel and promising source of pharmaceuticals for the treatment of disorders that might benefit from a reduction in endocannabinoid tone, such as hyperphagia in obese subjects.Experimental ApproachThree new fluorophosphonate compounds O‐7458, O‐7459 and O‐7460 were synthesized and characterized in various enzymatic assays. The effects of O‐7460 on high‐fat diet intake were tested in mice.Key ResultsOf the new compounds, O‐7460 exhibited the highest potency (IC50 = 690 nM) against the human recombinant DAGLα, and selectivity (IC50 > 10 μM) towards COS‐7 cell and human monoacylglycerol lipase (MAGL), and rat brain fatty acid amide hydrolase. Competitive activity‐based protein profiling confirmed that O‐7460 inhibits mouse brain MAGL only at concentrations ≥10 μM, and showed that this compound has only one major ‘off‐target’, that is, the serine hydrolase KIAA1363. O‐7460 did not exhibit measurable affinity for human recombinant CB1 or CB2 cannabinoid receptors (Ki > 10 μM). In mouse neuroblastoma N18TG2 cells stimulated with ionomycin, O‐7460 (10 μM) reduced 2‐AG levels. When administered to mice, O‐7460 dose‐dependently (0–12 mg·kg−1, i.p.) inhibited the intake of a high‐fat diet over a 14 h observation period, and, subsequently, slightly but significantly reduced body weight.Conclusions and ImplicationsO‐7460 might be considered a useful pharmacological tool to investigate further the role played by 2‐AG both in vitro and in vivo under physiological as well as pathological conditions.Linked ArticlesThis article is part of a themed section on Cannabinoids. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.169.issue‐4 & http://dx.doi.org/10.1111/bph.2012.167.issue‐8

  DOI：

  10.1111/bph.12013

文献信息

• A novel fluorophosphonate inhibitor of the biosynthesis of the endocannabinoid 2-arachidonoylglycerol with potential anti-obesity effects
  作者：Tiziana Bisogno、Anu Mahadevan、Roberto Coccurello、Jae Won Chang、Marco Allarà、Yugang Chen、Giacomo Giacovazzo、Aron Lichtman、Benjamin Cravatt、Anna Moles、Vincenzo Di Marzo

  DOI：10.1111/bph.12013

  日期：2013.6

  Background and PurposeThe development of potent and selective inhibitors of the biosynthesis of the endocannabinoid 2‐arachidonoylglycerol (2‐AG) via DAG lipases (DAGL) α and β is just starting to be considered as a novel and promising source of pharmaceuticals for the treatment of disorders that might benefit from a reduction in endocannabinoid tone, such as hyperphagia in obese subjects.Experimental ApproachThree new fluorophosphonate compounds O‐7458, O‐7459 and O‐7460 were synthesized and characterized in various enzymatic assays. The effects of O‐7460 on high‐fat diet intake were tested in mice.Key ResultsOf the new compounds, O‐7460 exhibited the highest potency (IC50 = 690 nM) against the human recombinant DAGLα, and selectivity (IC50 > 10 μM) towards COS‐7 cell and human monoacylglycerol lipase (MAGL), and rat brain fatty acid amide hydrolase. Competitive activity‐based protein profiling confirmed that O‐7460 inhibits mouse brain MAGL only at concentrations ≥10 μM, and showed that this compound has only one major ‘off‐target’, that is, the serine hydrolase KIAA1363. O‐7460 did not exhibit measurable affinity for human recombinant CB1 or CB2 cannabinoid receptors (Ki > 10 μM). In mouse neuroblastoma N18TG2 cells stimulated with ionomycin, O‐7460 (10 μM) reduced 2‐AG levels. When administered to mice, O‐7460 dose‐dependently (0–12 mg·kg−1, i.p.) inhibited the intake of a high‐fat diet over a 14 h observation period, and, subsequently, slightly but significantly reduced body weight.Conclusions and ImplicationsO‐7460 might be considered a useful pharmacological tool to investigate further the role played by 2‐AG both in vitro and in vivo under physiological as well as pathological conditions.Linked ArticlesThis article is part of a themed section on Cannabinoids. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.169.issue‐4 & http://dx.doi.org/10.1111/bph.2012.167.issue‐8