(1-{4-[2-(3,3-dimethylpiperazin-1-yl)-1H-benzimidazol-1-yl]piperidin-1-yl}cyclooctyl)methanol | 1258304-86-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: (1-{4-[2-(3,3-dimethylpiperazin-1-yl)-1H-benzimidazol-1-yl]piperidin-1-yl}cyclooctyl)methanol
• 英文别名: [1-[4-[2-(3,3-dimethylpiperazin-1-yl)benzimidazol-1-yl]piperidin-1-yl]cyclooctyl]methanol
• CAS: 1258304-86-7
• 化学式: C₂₇H₄₃N₅O
• 分子量: 453.671
• InChiKey: KQDFWEOLSLYTJB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  33
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.74
• 拓扑面积：
  56.6
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  (1-{4-[2-(4-benzyl-3,3-dimethylpiperazin-1-yl)-1H-benzimidazol-1-yl]piperidin-1-yl}cyclooctyl)methanol 在 氢气 、 palladium(II) hydroxide 作用下， 20.0 ℃ 、101.33 kPa 条件下， 反应 48.0h， 以80%的产率得到(1-{4-[2-(3,3-dimethylpiperazin-1-yl)-1H-benzimidazol-1-yl]piperidin-1-yl}cyclooctyl)methanol
  参考文献：
  名称：

  Discovery of {1-[4-(2-{hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}-1H-benzimidazol-1-yl)piperidin-1-yl]cyclooctyl}methanol, systemically potent novel non-peptide agonist of nociceptin/orphanin FQ receptor as analgesic for the treatment of neuropathic pain: Design, synthesis, and structure–activity relationships

  摘要：

  Neuropathic pain is a serious chronic disorder caused by lesion or dysfunction in the nervous systems. Endogenous nociceptin/orphanin FQ (N/OFQ) peptide and N/OFQ peptide (NOP) receptor [or opioidreceptor-like-1 (ORL1) receptor] are located in the central and peripheral nervous systems, the immune systems, and peripheral organs, and have a crucial role in the pain sensory system. Indeed, peripheral or intrathecal N/OFQ has displayed antinociceptive activities in neuropathic pain models, and inhibitory effects on pain-related neurotransmitter releases and on synaptic transmissions of C-and A delta-fibers. In this study, design, synthesis, and structure-activity relationships of peripheral/spinal cord-targeting non-peptide NOP receptor agonist were investigated for the treatment of neuropathic pain, which resulted in the discovery of highly selective and potent novel NOP receptor full agonist {1-[4-(2-{hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}-1H-benzimidazol-1-yl)piperidin-1-yl]cyclooctyl}methanol 1 (HPCOM) as systemically (subcutaneously) potent new-class analgesic. Thus, 1 demonstrates dose-dependent inhibitory effect against mechanical allodynia in chronic constriction injury-induced neuropathic pain model rats, robust metabolic stability and little hERG potassium ion channel binding affinity, with its unique and potentially safe profiles and mechanisms, which were distinctive from those of N/OFQ in terms of site-differential effects. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2010.07.034

文献信息

• Discovery of {1-[4-(2-{hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}-1H-benzimidazol-1-yl)piperidin-1-yl]cyclooctyl}methanol, systemically potent novel non-peptide agonist of nociceptin/orphanin FQ receptor as analgesic for the treatment of neuropathic pain: Design, synthesis, and structure–activity relationships
  作者：Shigeo Hayashi、Eriko Nakata、Asato Morita、Kunihiko Mizuno、Kenzo Yamamura、Aki Kato、Katsuyo Ohashi

  DOI：10.1016/j.bmc.2010.07.034

  日期：2010.11

  Neuropathic pain is a serious chronic disorder caused by lesion or dysfunction in the nervous systems. Endogenous nociceptin/orphanin FQ (N/OFQ) peptide and N/OFQ peptide (NOP) receptor [or opioidreceptor-like-1 (ORL1) receptor] are located in the central and peripheral nervous systems, the immune systems, and peripheral organs, and have a crucial role in the pain sensory system. Indeed, peripheral or intrathecal N/OFQ has displayed antinociceptive activities in neuropathic pain models, and inhibitory effects on pain-related neurotransmitter releases and on synaptic transmissions of C-and A delta-fibers. In this study, design, synthesis, and structure-activity relationships of peripheral/spinal cord-targeting non-peptide NOP receptor agonist were investigated for the treatment of neuropathic pain, which resulted in the discovery of highly selective and potent novel NOP receptor full agonist 1-[4-(2-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}-1H-benzimidazol-1-yl)piperidin-1-yl]cyclooctyl}methanol 1 (HPCOM) as systemically (subcutaneously) potent new-class analgesic. Thus, 1 demonstrates dose-dependent inhibitory effect against mechanical allodynia in chronic constriction injury-induced neuropathic pain model rats, robust metabolic stability and little hERG potassium ion channel binding affinity, with its unique and potentially safe profiles and mechanisms, which were distinctive from those of N/OFQ in terms of site-differential effects. (C) 2010 Elsevier Ltd. All rights reserved.