N-[1-[[(氰基氨基)(5-喹啉亚氨基)甲基]氨基]-2,2-二甲基丙基]-3,4-二甲氧基苯乙酰胺 | 861393-28-4

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 中文名称: N-[1-[[(氰基氨基)(5-喹啉亚氨基)甲基]氨基]-2,2-二甲基丙基]-3,4-二甲氧基苯乙酰胺
• 中文别名: N-[1-[[(氰基氨基)(5-喹啉咪)甲基]氨基]-2,2-二甲基丙基]-3,4-二甲氧基-苯乙酰胺
• 英文名称: N-[1-({(cyanoimino)[(5-quinolinyl)amino]methyl}amino)-2,2-dimethylpropyl]-2-(3,4-dimethoxyphenyl)acetamide
• 英文别名: [N-(1-{[(cyanoimino)(5-quinolinylamino)methyl]amino}-2,2-dimethylpropyl)-2-(3,4-dimethoxyphenyl)acetamide]；N-[1-[[(cyanoamino)(5-quinolinylamino)methylene]amino]-2,2-dimethyl propyl]-3,4-dimethoxybenzeneacetamide；N-(1-{[(cyanoimino)(5-quinolinylamino)methyl]amino}-2,2-dimethylpropyl)-2-(3,4-dimethoxyphenyl)acetamide；A-740003；A 740003；A740003；N-[1-[[(cyanoamino)-(quinolin-5-ylamino)methylidene]amino]-2,2-dimethylpropyl]-2-(3,4-dimethoxyphenyl)acetamide
• CAS: 861393-28-4
• 化学式: C₂₆H₃₀N₆O₃
• 分子量: 474.563
• InChiKey: PUHSRMSFDASMAE-UHFFFAOYSA-N

物化性质

• 熔点：
  128-129 °C
• 密度：
  1.19±0.1 g/cm3(Predicted)
• 溶解度：
  DMSO：可溶，10mg/mL，澄清（加热）

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  35
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  121
• 氢给体数：
  3
• 氢受体数：
  6

制备方法与用途

生物活性

A-740003 是一种有效的、选择性的 P2X7 receptor 的竞争性拮抗剂，对大鼠和人的P2X7受体的IC50值分别为18 nM和40 nM。A-740003 可在分化的人THP-1细胞中有效地阻断激动剂诱发的 IL-1β 释放和孔形成，对应的IC50值分别为156 nM和92 nM。

靶点

Target	Value
rat P2X7 receptor (Cell-free assay)	18 nM
human P2X7 receptor (Cell-free assay)	40 nM
IL-1β pore formation (Cell-based assay)	92 nM
IL-1β release (Cell-based assay)	156 nM

体外研究

A 438079 or A 740003 (10 μM) significantly blocks the sustained phase of the BzATP-induced response. A-740003 infusion reduces SE-induced TNF-α expression in dentate granule cells. A-740003 infusions increases SE-induced neuronal death. A-740003 and A-438079 show significantly greater potency in blocking P2X7 receptor activation across all species compared with other antagonists. A-740003 and A-438079 show greater activity at rat and human, as compared with mouse P2X7 receptors. A-740003 potently blocks agonist-evoked IL-1β release with (IC ₅₀ =156 nM) and pore formation (IC ₅₀ =92 nM) in differentiated human THP-1 cells.

体内研究

Systemic administration of A-740003 produces dose-dependent antinociception in a spinal nerve ligation model (ED ₅₀ =19 mg/kg i.p.) in the rat. A-740003 also attenuates tactile allodynia in two other models of neuropathic pain, chronic constriction injury of the sciatic nerve and vincristine-induced neuropathy. In addition, A-740003 effectively reduces thermal hyperalgesia observed following intraplantar administration of carrageenan or complete Freund's adjuvant (ED ₅₀ =38-54 mg/kg i.p.). A-740003 is ineffective in attenuating acute thermal nociception in normal rats and does not alter motor performance at analgesic doses.

反应信息

• 作为产物：
  描述：

  N-[1-(1H-苯并三唑-1-基)-2,2-二甲基丙基]-3,4-二甲氧基苯乙酰胺 、 N-氰基-N'-5-喹啉胍 在 caesium carbonate 作用下， 以 乙腈 为溶剂， 反应 10.0h， 生成 N-[1-[[(氰基氨基)(5-喹啉亚氨基)甲基]氨基]-2,2-二甲基丙基]-3,4-二甲氧基苯乙酰胺
  参考文献：
  名称：

  Discovery and Biological Evaluation of Novel Cyanoguanidine P2X₇ Antagonists with Analgesic Activity in a Rat Model of Neuropathic Pain

  摘要：

  We disclose the design of a novel series of cyanoguanidines that are potent (IC50 similar or equal to 10-100 nM) and selective (>= 100-fold) P2X(7) receptor antagonists against the other P2 receptor subtypes such as the P2Y(2), P2X(4), and P2X(3). We also found that these P2X(7) antagonists effectively reduced nociception in a rat model of neuropathic pain (Chung model). Particularly, analogue 53 proved to be effective in the Chung model, with an ED50 of 38 mu mol/kg after intraperitoneal administration. In addition compound 53 exhibited antiallodynic effects following oral administration and maintained its efficacy following repeated administration in the Chung model. These results suggest an important role of P2X(7) receptors in neuropathic pain and therefore a potential use of P2X(7) antagonists as novel therapeutic tools for the treatment of this type of pain.

  DOI：

  10.1021/jm8015848

文献信息

• P2X7 antagonists for treating neuropathic pain
  申请人：Carroll A. William

  公开号：US20050171195A1

  公开（公告）日：2005-08-04

  The present invention discloses a method for treating neuropathic pain using compounds of formula I or compositions containing compounds of formula I.

  本发明公开了一种利用式I化合物或含有式I化合物的组合物治疗神经病性疼痛的方法。
• AURIS FORMULATIONS FOR TREATING OTIC DISEASES AND CONDITIONS
  申请人：LICHTER Jay

  公开号：US20090306225A1

  公开（公告）日：2009-12-10

  Disclosed herein are compositions and methods for the treatment of otic disorders with immunomodulating agents and auris pressure modulators. In these methods, the auris compositions and formulations are administered locally to an individual afflicted with an otic disorder, through direct application of the immunomodulating and/or auris pressure modulating compositions and formulations onto the auris media and/or auris interna target areas, or via perfusion into the auris media and/or auris interna structures.

  本文公开了使用免疫调节剂和耳压调节剂治疗耳部疾病的组合物和方法。在这些方法中，通过将免疫调节剂和/或耳压调节剂组合物和配方直接应用于耳媒介和/或耳内靶区，或通过灌注进入耳媒介和/或耳内结构，局部给患有耳部疾病的个体进行治疗。
• Auris Formulations for Treating Otic Diseases and Conditions
  申请人：Otonomy, Inc.

  公开号：US20160228357A1

  公开（公告）日：2016-08-11

  Disclosed herein are compositions and methods for the treatment of otic disorders with immunomodulating agents and auris pressure modulators. In these methods, the auris compositions and formulations are administered locally to an individual afflicted with an otic disorder, through direct application of the immunomodulating and/or auris pressure modulating compositions and formulations onto the auris media and/or auris interna target areas, or via perfusion into the auris media and/or auris interna structures.

  本文介绍了使用免疫调节剂和耳压调节剂治疗耳部疾病的组合物和方法。在这些方法中，通过直接将免疫调节剂和/或耳压调节剂组合物和配方局部应用于患有耳部疾病的个体的耳媒体和/或耳内靶区，或通过灌注到耳媒体和/或耳内结构中。
• MODULATORS OF PURINERGIC RECEPTORS AND RELATED IMMUNE CHECKPOINT FOR TREATING ACUTE RESPIRATORY DISTRESS SYNDROM
  申请人：Institut Gustave-Roussy

  公开号：EP3919062A1

  公开（公告）日：2021-12-08

  The inventors herein show that purinergic receptors regulate the conversion of macrophage pro-inflammatory reprogramming into anti-inflammatory phenotype in patients suffering from COVID-19 disease. Moreover, they show that P2Y receptor agonists repress NLRP3 inflammasome-dependent IL-1b secretion, but also impair the replication and the cytopathogenic effects of SARS-CoV-2. These results therefore suggest that some purinergic receptors agonists can treat acute lung injury and respiratory disease that are associated with SARS-CoV-2 infection. In addition, their results show that antagonists of the purinergic receptors P2X impair the replication of said virus. The present invention therefore proposes to use purinergic receptors modulators and NLR3-P2Y2R immune checkpoint modulators to treat patients suffering from a virus-induced acute respiratory distress syndrome.

  本发明人在此表明，嘌呤能受体可调节 COVID-19 疾病患者的巨噬细胞促炎重编程转化为抗炎表型。此外，他们还发现 P2Y 受体激动剂能抑制 NLRP3 炎症体依赖性 IL-1b 的分泌，还能损害 SARS-CoV-2 的复制和细胞致病作用。因此，这些结果表明，一些嘌呤能受体激动剂可以治疗与SARS-CoV-2感染相关的急性肺损伤和呼吸系统疾病。此外，他们的研究结果表明，嘌呤能受体 P2X 的拮抗剂会损害上述病毒的复制。因此，本发明建议使用嘌呤能受体调节剂和 NLR3-P2Y2R 免疫检查点调节剂来治疗由病毒引起的急性呼吸窘迫综合征患者。
• Auris formulations for treating otic diseases and conditions
  申请人：Otonomy, Inc.

  公开号：US10272034B2

  公开（公告）日：2019-04-30

  Disclosed herein are compositions and methods for the treatment of otic disorders with immunomodulating agents and auris pressure modulators. In these methods, the auris compositions and formulations are administered locally to an individual afflicted with an otic disorder, through direct application of the immunomodulating and/or auris pressure modulating compositions and formulations onto the auris media and/or auris interna target areas, or via perfusion into the auris media and/or auris interna structures.

  本文公开了使用免疫调节剂和耳压调节剂治疗耳部疾病的组合物和方法。在这些方法中，通过将免疫调节剂和/或免疫调节压力调节剂组合物和制剂直接施用到耳道介质和/或耳道间质目标区域，或通过灌注到耳道介质和/或耳道间质结构中，对耳道疾病患者进行局部给药。