1-(1-(1-(4-fluorophenyl)ethyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one | 6440-42-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 英文名称: 1-(1-(1-(4-fluorophenyl)ethyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one
• 英文别名: fluorphine；1-{1-[1-(4-fluoro-phenyl)-ethyl]-piperidin-4-yl}-1,3-dihydro-benzoimidazol-2-one；Fluorphine；3-[1-[1-(4-fluorophenyl)ethyl]piperidin-4-yl]-1H-benzimidazol-2-one
• CAS: 6440-42-2
• 化学式: C₂₀H₂₂FN₃O
• 分子量: 339.413
• InChiKey: ZIGVSUYDKUDHPY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  25
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  35.6
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  4-氟苯乙酮 、 4-（2-酮酸-1-苯并咪唑）哌啶 在 titanium(IV) isopropylate 、 三乙酰氧基硼氢化钠 作用下， 以 四氢呋喃 为溶剂， 反应 5.0h， 以51%的产率得到1-(1-(1-(4-fluorophenyl)ethyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one
  参考文献：
  名称：

  Optimization of a Series of Mu Opioid Receptor (MOR) Agonists with High G Protein Signaling Bias

  摘要：

  While mu opioid receptor (MOR) agonists are especially effective as broad-spectrum pain relievers, it has been exceptionally difficult to achieve a clear separation of analgesia from many problematic side effects. Recently, many groups have sought MOR agonists that induce minimal beta arrestin-mediated signaling because MOR agonist-treated beta arrestin2 knockout mice were found to display enhanced antinociceptive effects with significantly less respiratory depression and tachyphylaxis. Substantial data now exists to support the premise that G protein signaling biased MOR agonists can be effective analgesic agents. We recently showed that, within a chemical series, the degree of bias correlates linearly with the magnitude of the respiratory safety index. Herein we describe the synthesis and optimization of piperidine benzimidazolone MOR agonists that together display a wide range of bias (G/beta arr2). We identify structural features affecting potency and maximizing bias and show that many compounds have desirable properties, such as long half-lives and high brain penetration.

  DOI：

  10.1021/acs.jmedchem.8b01136

文献信息

• Optimization of a Series of Mu Opioid Receptor (MOR) Agonists with High G Protein Signaling Bias
  作者：Nicole M. Kennedy、Cullen L. Schmid、Nicolette C. Ross、Kimberly M. Lovell、Zhizhou Yue、Yen Ting Chen、Michael D. Cameron、Laura M. Bohn、Thomas D. Bannister

  DOI：10.1021/acs.jmedchem.8b01136

  日期：2018.10.11

  While mu opioid receptor (MOR) agonists are especially effective as broad-spectrum pain relievers, it has been exceptionally difficult to achieve a clear separation of analgesia from many problematic side effects. Recently, many groups have sought MOR agonists that induce minimal beta arrestin-mediated signaling because MOR agonist-treated beta arrestin2 knockout mice were found to display enhanced antinociceptive effects with significantly less respiratory depression and tachyphylaxis. Substantial data now exists to support the premise that G protein signaling biased MOR agonists can be effective analgesic agents. We recently showed that, within a chemical series, the degree of bias correlates linearly with the magnitude of the respiratory safety index. Herein we describe the synthesis and optimization of piperidine benzimidazolone MOR agonists that together display a wide range of bias (G/beta arr2). We identify structural features affecting potency and maximizing bias and show that many compounds have desirable properties, such as long half-lives and high brain penetration.