1-(4-methoxybenzyl)-5-{2-[(4-methoxybenzyl)-5-{[1-(4-methoxybenzyl)-5-nitro-2H-pyrazole-3-carbonyl]pyrazol-3-carbonyl]amino}-2H-pyrazole-3-carbonylamino}-2H-pyrazole-3-carboxylic acid methyl ester | 625386-19-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: 1-(4-methoxybenzyl)-5-{2-[(4-methoxybenzyl)-5-{[1-(4-methoxybenzyl)-5-nitro-2H-pyrazole-3-carbonyl]pyrazol-3-carbonyl]amino}-2H-pyrazole-3-carbonylamino}-2H-pyrazole-3-carboxylic acid methyl ester
• 英文别名: 1-(4-methoxybenzyl)-3-(1-(4-methoxybenzyl)-3-(1-(4-methoxybenzyl)-3-nitro-1H-pyrazole-5-carboxamido)-1H-pyrazole-5-carboxamido)-1H-pyrazole-5-carboxylic acid methyl ester；3-(3-(3-nitro-1-(4-methoxybenzyl)-1H-pyrazole-5-carboxamido)-1-(4-methoxybenzyl)-1H-pyrazole-5-carboxamido)-1-(4-methoxybenzyl)-1H-pyrazole-5-carboxylic acid methyl ester；methyl 2-[(4-methoxyphenyl)methyl]-5-[[2-[(4-methoxyphenyl)methyl]-5-[[2-[(4-methoxyphenyl)methyl]-5-nitropyrazole-3-carbonyl]amino]pyrazole-3-carbonyl]amino]pyrazole-3-carboxylate
• CAS: 625386-19-8
• 化学式: C₃₇H₃₅N₉O₉
• 分子量: 749.74
• InChiKey: GXSXHRVEBNSPDA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  55
• 可旋转键数：
  15
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  212
• 氢给体数：
  2
• 氢受体数：
  12

反应信息

• 作为反应物：
  描述：

  1-(4-methoxybenzyl)-5-{2-[(4-methoxybenzyl)-5-{[1-(4-methoxybenzyl)-5-nitro-2H-pyrazole-3-carbonyl]pyrazol-3-carbonyl]amino}-2H-pyrazole-3-carbonylamino}-2H-pyrazole-3-carboxylic acid methyl ester 在 甲醇 、 水 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 lithium hydroxide 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 66.0h， 生成 1-(1-(4-methoxybenzyl)-3-(1-(4-methoxybenzyl)-3-(1-(4-methoxybenzyl)-3-nitro-1H-pyrazole-5-carboxamido)-1H-pyrazole-5-carboxamido)-1H-pyrazole-5-yl)-1-oxo-5,8,11-trioxa-2-azatridecan-13-oic acid
  参考文献：
  名称：

  Rational Design of β-Sheet Ligands Against Aβ₄₂-Induced Toxicity

  摘要：

  A beta-sheet-binding scaffold was equipped with long-range chemical groups for tertiary contacts toward specific regions of the Alzheimer's A beta fibril. The new constructs contain a trimeric aminopyrazole carboxylic acid, elongated with a C-terminal binding site, whose influence on the aggregation behavior of the A beta(42) peptide was studied. MD simulations after trimer docking to the anchor point (F19/F20) suggest distinct groups of complex structures each of which featured additional specific interactions with characteristic A beta regions. Members of each group also displayed a characteristic pattern in their antiaggregational behavior toward A beta. Specifically, remote lipophilic moieties such as a dodecyl, cyclohexyl, or LPFFD fragment can form dispersive interactions with the nonpolar cluster of amino acids between I31 and V36. They were shown to strongly reduce Thioflavine T (ThT) fluorescence and protect cells from A beta lesions (MTT viability assays). Surprisingly, very thick fibrils and a high beta-sheet content were detected in transmission electron microscopy (TEM) and CD spectroscopic experiments. On the other hand, distant single or multiple lysines which interact with the ladder of stacked E22 residues found in A beta fibrils completely dissolve existing beta-sheets (ThT, CD) and lead to unstructured, nontoxic material (TEM, MTT). Finally, the triethyleneglycol spacer between heterocyclic beta-sheet ligand and appendix was found to play an active role in destabilizing the turn of the U-shaped protofilament. Fluorescence correlation spectroscopy (FCS) and sedimentation velocity analysis (SVA) provided experimental evidence for some smaller benign aggregates of very thin, delicate structure (TEM, MTT). A detailed investigation by dynamic light scattering (DLS) and other methods proved that none of the new ligands acts as a colloid. The evolving picture for the disaggregation mechanism by these new hybrid ligands implies transformation of well-ordered fibrils into less structured aggregates with a high molecular weight. In the few cases where fibrillar components remain, these display a significantly altered morphology and have lost their acute cellular toxicity.

  DOI：

  10.1021/ja107675n
• 作为产物：
  描述：

  5-amino-2-(4-methoxybenzyl)-2H-pyrazole-3-carboxylic acid methyl ester 在 palladium on activated charcoal 2-氯-1-甲基吡啶碘化物 、 氢气 、 N,N-二异丙基乙胺 、 chlorotri(pyrrolidin-1-yl)phosphonium hexafluorophosphate 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 氯仿 为溶剂， 反应 117.0h， 生成 1-(4-methoxybenzyl)-5-{2-[(4-methoxybenzyl)-5-{[1-(4-methoxybenzyl)-5-nitro-2H-pyrazole-3-carbonyl]pyrazol-3-carbonyl]amino}-2H-pyrazole-3-carbonylamino}-2H-pyrazole-3-carboxylic acid methyl ester
  参考文献：
  名称：

  Aminopyrazole Oligomers for β-SheetStabilization of Peptides

  摘要：

  本文介绍了利用设计的人工配体稳定δ-片材的一般概念。这些配体有两个主要特征：它们含有酰化的 3-氨基吡唑，具有 DAD 氢键供体和受体模式；它们被合成为低聚物，以增加它们与δ-片构象中的肽的氢键相互作用。二聚氨基吡唑可通过 N1-Boc 保护的氨基吡唑衍生物 1 与几种二氯酸反应，然后用三氟乙酸进行标准脱保护处理而获得。对于低聚物，对新的吡唑氨基酸进行 N1-PMB 保护，然后使用 PyClop 或 Mukaiyama 试剂与肽偶联进行迭代扩展，最终得到目标化合物。随后，所有的保护基团都在最后一步用温三氟乙酸进行脱保护。对两个二聚关键化合物 3b 和 3f 进行了不同温度下的核磁共振、NOESY 实验和 X 射线晶体学研究，以阐明它们在溶液和固体状态下的构象偏好。所有方法得出的结果都是一样的：两种配体都采用具有高度预取向性的扁平构象和正确的 DAD 模式，以便与扩展构象中的肽发生最佳相互作用。用朊病毒蛋白和阿尔茨海默氏症肽 Aβ (1-40) 进行的聚合试验表明，一些二聚体和寡聚体配体在极低浓度下就能产生很好的效果。

  DOI：

  10.1055/s-2003-41031

文献信息

• Synthesis and Binding Studies of Alzheimer Ligands on Solid Support
  作者：Petra Rzepecki、Nina Geib、Manuel Peifer、Frank Biesemeier、Thomas Schrader

  DOI：10.1021/jo061918x

  日期：2007.5.1

  Aminopyrazole derivatives constitute the first class of nonpeptidic rationally designed β-sheet ligands. Here we describe a double solid-phase protocol for both synthesis and affinity testing. The presented solid-phase synthesis of four types of hybrid compounds relies on the Fmoc strategy and circumvents subsequent HPLC purification by precipitating the final product from organic solution in pure

  氨基吡唑衍生物构成第一类合理设计的非肽类β-折叠配体。在这里，我们描述了用于合成和亲和力测试的双重固相方案。所提出的四种杂合化合物的固相合成依赖于Fmoc策略，并通过从有机溶液中以纯净形式沉淀出最终产物来规避随后的HPLC纯化。具有内部二肽和四肽桥的六肽和八肽侧基现在可以高产率地用于化合物文库的组合合成，以进行高通量筛选。耐酸性PAM上的固相肽合成（SPPS）使我们在PMB脱保护后，可以将固定状态下的游离氨基吡唑结合位点进行荧光标记肽的珠上检测。从荧光发射强度的降低，可以通过简单地应用质量作用定律，通过参考曲线计算出各个结合常数。令人高兴的是，即使对于几乎不溶于水的那些配体，也可以定量地监测宿主/客体的复合。
• [EN] NEW COMPOUNDS FOR THE TREATMENT OF DISEASES RELATED TO PROTEIN MISFOLDING<br/>[FR] NOUVEAUX COMPOSÉS POUR LE TRAITEMENT DE MALADIES LIÉES À UN MAUVAIS REPLIEMENT DE PROTÉINES
  申请人：UNIV DUISBURG ESSEN

  公开号：WO2011050864A1

  公开（公告）日：2011-05-05

  The present invention relates to the field of protein misfolding diseases and thus to diseases which are associated with or induced by abnormal or pathogenic three-dimensional folding of proteins and/or peptides or which are linked to pathogenic conformational changes of proteins and/or peptides, such as Alzheimer's disease. Particularly, the present invention provides novel trimeric pyrazole compounds, which exhibit a therapeutic effectiveness in regard to the aforementioned protein misfolding diseases, and refers to their use for the treatment of such protein misfolding diseases, especially neurodegenerative diseases as well as to medicaments or pharmaceutical compositions comprising these compounds.

  本发明涉及蛋白质错折疾病领域，因此涉及与异常或致病性蛋白质和/或肽的三维折叠相关或诱导的疾病，或与致病性蛋白质和/或肽的构象变化相关的疾病，如阿尔茨海默病。具体地，本发明提供了新型三聚吡唑化合物，这些化合物在治疗上述蛋白质错折疾病方面表现出治疗有效性，并涉及其用于治疗此类蛋白质错折疾病，特别是神经退行性疾病，以及包含这些化合物的药物或制剂组合物。
• COMPOUNDS FOR THE TREATMENT OF DISEASES RELATED TO PROTEIN MISFOLDING
  申请人：Schrader Thomas

  公开号：US20120270795A1

  公开（公告）日：2012-10-25

  The present invention relates to the field of protein misfolding diseases and thus to diseases which are associated with or induced by abnormal or pathogenic three-dimensional folding of proteins and/or peptides or which are linked to pathogenic conformational changes of proteins and/or peptides, such as Alzheimer's disease. Particularly, the present invention provides novel trimeric pyrazole compounds, which exhibit a therapeutic effectiveness in regard to the aforementioned protein misfolding diseases, and refers to their use for the treatment of such protein misfolding diseases, especially neurodegenerative diseases as well as to medicaments or pharmaceutical compositions comprising these compounds.

  本发明涉及蛋白质错折疾病领域，因此涉及与蛋白质和/或肽的异常或致病三维折叠相关或诱导的疾病，以及与蛋白质和/或肽的致病构象变化相关的疾病，如阿尔茨海默病。特别地，本发明提供了新型三聚吡唑化合物，其在治疗上述蛋白质错折疾病方面具有治疗效果，并涉及其用于治疗这种蛋白质错折疾病，特别是神经退行性疾病，以及包含这些化合物的药物或制药组合物。
• Compounds for the treatment of diseases related to protein misfolding
  申请人：Schrader Thomas

  公开号：US08481494B2

  公开（公告）日：2013-07-09

  The present invention relates to the field of protein misfolding diseases and thus to diseases which are associated with or induced by abnormal or pathogenic three-dimensional folding of proteins and/or peptides or which are linked to pathogenic conformational changes of proteins and/or peptides, such as Alzheimer's disease. Particularly, the present invention provides novel trimeric pyrazole compounds, which exhibit a therapeutic effectiveness in regard to the aforementioned protein misfolding diseases, and refers to their use for the treatment of such protein misfolding diseases, especially neurodegenerative diseases as well as to medicaments or pharmaceutical compositions comprising these compounds.

  本发明涉及蛋白质错折性疾病领域，因此涉及与或由蛋白质和/或肽的异常或致病性三维折叠相关或诱导的疾病，或与蛋白质和/或肽的致病性构象变化相关的疾病，如阿尔茨海默病等。特别地，本发明提供了新型三聚吡唑化合物，其在上述蛋白质错折性疾病方面表现出治疗有效性，并涉及其用于治疗此类蛋白质错折性疾病，特别是神经退行性疾病，以及包括这些化合物的药物或制剂。
• US8481494B2
  申请人：——

  公开号：US8481494B2

  公开（公告）日：2013-07-09