(3S)-1-(pent-4-enoyl)-[(1R)-(4-phenylbutoxy)ethyl]azetidin-2-one | 1335557-85-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 内酰胺类
• 英文名称: (3S)-1-(pent-4-enoyl)-[(1R)-(4-phenylbutoxy)ethyl]azetidin-2-one
• 英文别名: (3S)-1-pent-4-enoyl-3-[(1R)-1-(4-phenylbutoxy)ethyl]azetidin-2-one
• CAS: 1335557-85-1
• 化学式: C₂₀H₂₇NO₃
• 分子量: 329.439
• InChiKey: JPZQJQBRTDSJSO-AEFFLSMTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  24
• 可旋转键数：
  10
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  46.6
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  4-苯基-1-丁基溴 在 吡啶 、 ammonium cerium (IV) nitrate 、 sodium hydride 、 potassium iodide 作用下， 以 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 24.25h， 生成 (3S)-1-(pent-4-enoyl)-[(1R)-(4-phenylbutoxy)ethyl]azetidin-2-one 、 (3R)-1-(pent-4-enoyl)-[(1R)-(4-phenylbutoxy)ethyl]azetidin-2-one
  参考文献：
  名称：

  SAR and LC/MS Studies of β-Lactamic Inhibitors of Human Fatty Acid Amide Hydrolase (hFAAH): Evidence of a Nonhydrolytic Process

  摘要：

  The endocannabinoid hydrolyzing enzyme FAAH uses a nonclassical catalytic triad (namely, Ser-Ser-Lys instead of Ser-Asp-His) to cleave its endogenous substrates. Because inhibiting FAAH has a clear therapeutic potential, we previously developed beta-lactam-type inhibitors of hFAAH. Here, we report the synthesis of five novel derivatives (5-9) of our lead compound 1-(pent-4-enoyl)-3 (S)-[1(R)-(4-phenylbutanoyloxy)-ethyl] azetidin-2-one (4, IC50 = 5 nM) obtained via the systematic replacement of one to three carbonyls by methylene groups. The SAR results showed that the imide, but not the lactam, function is essential to the inhibition of hFAAH. We also performed LC/MS analysis following incubation of our inhibitors with hFAAH or mouse liver. We demonstrated that hFAAH interacts with these beta-lactam-type inhibitors but, unexpectedly, does not open the beta-lactam moiety. This mechanism seems to be unique to FAAH because the beta-lactam function of the inhibitors is hydrolyzed when they are incubated in the presence of the serine hydrolases expressed in the mouse liver. Finally, we confirmed these results by showing that a highly selective FAAH inhibitor (PF-750) does not prevent this hydrolysis by liver homogenates.

  DOI：

  10.1021/jm200723m

文献信息

• SAR and LC/MS Studies of β-Lactamic Inhibitors of Human Fatty Acid Amide Hydrolase (<i>h</i>FAAH): Evidence of a Nonhydrolytic Process
  作者：Marion Feledziak、Giulio G. Muccioli、Didier M. Lambert、Jacqueline Marchand-Brynaert

  DOI：10.1021/jm200723m

  日期：2011.10.13

  The endocannabinoid hydrolyzing enzyme FAAH uses a nonclassical catalytic triad (namely, Ser-Ser-Lys instead of Ser-Asp-His) to cleave its endogenous substrates. Because inhibiting FAAH has a clear therapeutic potential, we previously developed beta-lactam-type inhibitors of hFAAH. Here, we report the synthesis of five novel derivatives (5-9) of our lead compound 1-(pent-4-enoyl)-3 (S)-[1(R)-(4-phenylbutanoyloxy)-ethyl] azetidin-2-one (4, IC50 = 5 nM) obtained via the systematic replacement of one to three carbonyls by methylene groups. The SAR results showed that the imide, but not the lactam, function is essential to the inhibition of hFAAH. We also performed LC/MS analysis following incubation of our inhibitors with hFAAH or mouse liver. We demonstrated that hFAAH interacts with these beta-lactam-type inhibitors but, unexpectedly, does not open the beta-lactam moiety. This mechanism seems to be unique to FAAH because the beta-lactam function of the inhibitors is hydrolyzed when they are incubated in the presence of the serine hydrolases expressed in the mouse liver. Finally, we confirmed these results by showing that a highly selective FAAH inhibitor (PF-750) does not prevent this hydrolysis by liver homogenates.