4-(8-butoxy-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-7-yl)-N-(5-tert-butyl-2-hydroxyphenyl)butanamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 英文名称: 4-(8-butoxy-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-7-yl)-N-(5-tert-butyl-2-hydroxyphenyl)butanamide
• 英文别名: 4-(8-butoxy-1,3-dimethyl- 2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(5-(tert-butyl)-2-hydroxyphenyl)butanamide；4-(8-butoxy-1,3-dimethyl-2,6-dioxopurin-7-yl)-N-(5-tert-butyl-2-hydroxyphenyl)butanamide
• 化学式: C₂₅H₃₅N₅O₅
• 分子量: 485.583
• InChiKey: PAOJOHTYHBWEAR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  35
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  117
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  8-溴茶碱 在 苄基三乙基氯化铵 、 potassium carbonate 、 N,N'-羰基二咪唑 、 potassium hydroxide 作用下， 以 水 、 N,N-二甲基甲酰胺 、 丙酮 为溶剂， 反应 102.5h， 生成 4-(8-butoxy-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-7-yl)-N-(5-tert-butyl-2-hydroxyphenyl)butanamide
  参考文献：
  名称：

  1,3-二甲基-2,6-二氧杂嘌呤-7-烷基烷基羧酸的新型酰胺衍生物作为多功能TRPA1拮抗剂和PDE4 / 7抑制剂：治疗疼痛的新方法

  摘要：

  合成并分析了一系列使用基于结构的计算方法设计的1,3-二甲基-2,6-二氧杂嘌呤-7-基-烷基羧酸的新型酰胺衍生物，以评估其阻断人TRPA1通道和抑制PDE4B /的能力。 7A活动。我们鉴定了与HC-030031相比，对TRPA1具有更高效力的化合物16和27。反过来，化合物36是最有前途的多功能TRPA1拮抗剂和PDE4B / 7A双重抑制剂，其IC 50值分别在参考咯利普兰和BRL-50481的范围内。化合物36作为TRPA1 / PDE4B / PDE7A的组合配体，其特征在于与16和1627，在给定的蛋白质靶标上。两种cAMP特异性PDE同工酶的抑制作用在体内可产生36 种强的抗TNF-α作用。此外，在疼痛和发炎的动物模型（小鼠中的福尔马林测试和大鼠中的角叉菜胶诱发的爪水肿）中观察到了强效的36消炎和镇痛效果。该化合物在化疗诱导的小鼠周围神经病变的早期也显示出显着的抗痛觉过敏特性

  DOI：

  10.1016/j.ejmech.2018.09.021

文献信息

• Novel amide derivatives of 1,3-dimethyl-2,6-dioxopurin-7-yl-alkylcarboxylic acids as multifunctional TRPA1 antagonists and PDE4/7 inhibitors: A new approach for the treatment of pain
  作者：Grażyna Chłoń-Rzepa、Marietta Ślusarczyk、Agnieszka Jankowska、Alicja Gawalska、Adam Bucki、Marcin Kołaczkowski、Artur Świerczek、Krzysztof Pociecha、Elżbieta Wyska、Małgorzata Zygmunt、Grzegorz Kazek、Kinga Sałat、Maciej Pawłowski

  DOI：10.1016/j.ejmech.2018.09.021

  日期：2018.10

  promising multifunctional TRPA1 antagonist and PDE4B/7A dual inhibitor with IC50 values in the range of that of the reference rolipram and BRL-50481, respectively. Compound 36 as a combined TRPA1/PDE4B/PDE7A ligand was characterized by a distinct binding mode in comparison to 16 and 27, in the given protein targets. The inhibition of both cAMP-specific PDE isoenzymes resulted in a strong anti-TNF-α effect

  合成并分析了一系列使用基于结构的计算方法设计的1,3-二甲基-2,6-二氧杂嘌呤-7-基-烷基羧酸的新型酰胺衍生物，以评估其阻断人TRPA1通道和抑制PDE4B /的能力。 7A活动。我们鉴定了与HC-030031相比，对TRPA1具有更高效力的化合物16和27。反过来，化合物36是最有前途的多功能TRPA1拮抗剂和PDE4B / 7A双重抑制剂，其IC 50值分别在参考咯利普兰和BRL-50481的范围内。化合物36作为TRPA1 / PDE4B / PDE7A的组合配体，其特征在于与16和1627，在给定的蛋白质靶标上。两种cAMP特异性PDE同工酶的抑制作用在体内可产生36 种强的抗TNF-α作用。此外，在疼痛和发炎的动物模型（小鼠中的福尔马林测试和大鼠中的角叉菜胶诱发的爪水肿）中观察到了强效的36消炎和镇痛效果。该化合物在化疗诱导的小鼠周围神经病变的早期也显示出显着的抗痛觉过敏特性
• Novel phosphodiesterases inhibitors from the group of purine-2,6-dione derivatives as potent modulators of airway smooth muscle cell remodelling
  作者：Katarzyna Wójcik-Pszczoła、Grażyna Chłoń-Rzepa、Agnieszka Jankowska、Eugenie Ellen、Artur Świerczek、Krzysztof Pociecha、Paulina Koczurkiewicz、Kamil Piska、Anna Gawędzka、Elżbieta Wyska、Małgorzata Knapik-Czajka、Elżbieta Pękala、Reinoud Gosens

  DOI：10.1016/j.ejphar.2019.172779

  日期：2019.12

  Airway remodelling (AR) is an important pathological feature of chronic asthma and chronic obstructive pulmonary disease. The etiology of AR is complex and involves both lung structural and immune cells. One of the main contributors to airway remodelling is the airway smooth muscle (ASM), which is thickened by asthma, becomes more contractile and produces more extracellular matrix. As a second messenger, adenosine 3',5'-cyclic monophosphate (cAMP) has been shown to contribute to ASM cell (ASMC) relaxation as well as to anti-remodelling effects in ASMC. Phosphodiesterase (PDE) inhibitors have drawn attention as an interesting new group of potential anti-inflammatory and anti-remodelling drugs. Recently, new hydrazide and amide purine-2,6-dione derivatives with anti-inflammatory properties have been synthesized by our team (compounds 1 and 2). We expanded our study of their PDE selectivity profile, ability to increase intracellular cAMP levels, metabolic stability and, above all, their capacity to modulate cell responses associated with ASMC remodelling. The results show that both compounds have subtype specificity for several PDE isoforms (including inhibition of PDE1, PDE3, PDE4 and PDE7). Interestingly, such combined PDE subtype inhibition exerts improved anti-remodelling efficacies against several ASMC-induced responses such as proliferation, contractility, extracellular matrix (ECM) protein expression and migration when compared to other non-selective and selective PDE inhibitors. Our findings open novel perspectives in the search for new chemical entities with dual anti-inflammatory and anti-remodelling profiles in the group of purine-2,6-dione derivatives as broad-spectrum PDE inhibitors.