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 ethyl ester | 1282034-86-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: 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 ethyl ester
• 英文别名: 1-(1-(4-methoxybenzyl)-3-(1-(4-methoxybenzyl)-3-(1-(4-methoxybenzyl)-3-nitro-1H-pyrazole-5-carboxamido)-1H-7-pyrazole-5-carboxamido)-1H-pyrazole-5-yI)-1-oxo-5,8,11-trioxa-2-azatridecan-13-oic acid ethyl ester；Ethyl 2-[2-[2-[2-[[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-carbonyl]amino]ethoxy]ethoxy]ethoxy]acetate；ethyl 2-[2-[2-[2-[[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-carbonyl]amino]ethoxy]ethoxy]ethoxy]acetate
• CAS: 1282034-86-9
• 化学式: C₄₆H₅₂N₁₀O₁₃
• 分子量: 952.978
• InChiKey: VERFGYTYHRSSAM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  69
• 可旋转键数：
  27
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  268
• 氢给体数：
  3
• 氢受体数：
  16

反应信息

• 作为反应物：
  描述：

  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 ethyl ester 在 甲醇 、 水 、 lithium hydroxide 作用下， 以 四氢呋喃 为溶剂， 反应 48.0h， 以92%的产率得到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：

  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 18.0h， 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 ethyl ester
  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

文献信息

• 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。
• US8481494B2
  申请人：——

  公开号：US8481494B2

  公开（公告）日：2013-07-09