1-(1-(4-bromo-2-fluorobenzyl)piperidin-4-yl)-5-chloro-1H-benzo[d]imidazol-2(3H)-one

• 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: 1-(1-(4-bromo-2-fluorobenzyl)piperidin-4-yl)-5-chloro-1H-benzo[d]imidazol-2(3H)-one
• 英文别名: 5-chloro-1-(1-(4-bromo-2-fluorobenzyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one；3-[1-[(4-bromo-2-fluorophenyl)methyl]piperidin-4-yl]-6-chloro-1H-benzimidazol-2-one
• 化学式: C₁₉H₁₈BrClFN₃O
• 分子量: 438.727
• InChiKey: WBECKUWCFNXRGX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  26
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  35.6
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  甲烷磺酸 、 1-(1-(4-bromo-2-fluorobenzyl)piperidin-4-yl)-5-chloro-1H-benzo[d]imidazol-2(3H)-one 以 乙醇 为溶剂， 反应 0.5h， 生成 5-chloro-1-(1-(4-bromo-2-fluorobenzyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one mesylate salt
  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
• 作为产物：
  描述：

  5-氯-2-氟硝基苯 在 三乙酰氧基硼氢化钠 、 potassium carbonate 、 一水合肼 、 溶剂黄146 、 三氟乙酸 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 水 、 二甲基亚砜 、 1,2-二氯乙烷 为溶剂， 反应 0.17h， 生成 1-(1-(4-bromo-2-fluorobenzyl)piperidin-4-yl)-5-chloro-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

• [EN] SIGNALING-BIASED MU OPIOID RECEPTOR AGONISTS<br/>[FR] AGONISTES DU RÉCEPTEUR OPIOÏDE MU À SIGNALISATION BIAISÉE
  申请人：SCRIPPS RESEARCH INST

  公开号：WO2017161017A1

  公开（公告）日：2017-09-21

  The invention provides -opioid receptor agonists that are analgesic agents and that promote diminished side effects relative to a comparably effective dose of morphine. The side effects that are absent or attenuated include one or more of the following: constipation, respiratory depression, tolerance, dependence, nausea, confusion, sedation, hypotension, and post-treatment withdrawal symptoms.

  该发明提供了-阿片受体激动剂，它们是镇痛剂，并且相对于相同有效剂量的吗啡，可以减少副作用。这些缺席或减弱的副作用包括以下一种或多种：便秘、呼吸抑制、耐受性、依赖性、恶心、困惑、嗜睡、低血压和治疗后戒断症状。
• Signaling-biased mu opioid receptor agonists
  申请人：THE SCRIPPS RESEARCH INSTITUTE

  公开号：US10751335B2

  公开（公告）日：2020-08-25

  The invention provides—opioid receptor agonists that are analgesic agents and that promote diminished side effects relative to a comparably effective dose of morphine. The side effects that are absent or attenuated include one or more of the following: constipation, respiratory depression, tolerance, dependence, nausea, confusion, sedation, hypotension, and post-treatment withdrawal symptoms.

  本发明提供的阿片受体激动剂是一种镇痛剂，与同等有效剂量的吗啡相比，副作用较小。没有或减轻的副作用包括以下一种或多种：便秘、呼吸抑制、耐受性、依赖性、恶心、精神错乱、镇静、低血压和治疗后戒断症状。
• SIGNALING-BIASED MU OPIOID RECEPTOR AGONISTS
  申请人：The Scripps Research Institute

  公开号：EP3430007A1

  公开（公告）日：2019-01-23
• 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.