N-hydroxy-3-[4-[[[2-(1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide | 404951-52-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: N-hydroxy-3-[4-[[[2-(1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide
• 英文别名: (E)-N-Hydroxy-3-(4-{[2-(1H-indol-3-yl)-ethylamino]-methyl}-phenyl)-acrylamide；(E)-N-hydroxy-3-[4-[[2-(1H-indol-3-yl)ethylamino]methyl]phenyl]prop-2-enamide
• CAS: 404951-52-6
• 化学式: C₂₀H₂₁N₃O₂
• 分子量: 335.406
• InChiKey: ZLUZDKXBTNQWOL-MDZDMXLPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  25
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  77.2
• 氢给体数：
  4
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  环己酮 、 N-hydroxy-3-[4-[[[2-(1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide 在 sodium cyanoborohydride 作用下， 以 甲醇 为溶剂， 反应 4.0h， 生成 (E)-3-[4-({Cyclohexyl-[2-(1H-indol-3-yl)-ethyl]-amino}-methyl)-phenyl]-N-hydroxy-acrylamide
  参考文献：
  名称：

  N-Hydroxy-3-phenyl-2-propenamides as Novel Inhibitors of Human Histone Deacetylase with in Vivo Antitumor Activity:  Discovery of (2E)-N-Hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide (NVP-LAQ824)

  摘要：

  A series of N-hydroxy-3-phenyl-2-propenamides were prepared as novel inhibitors of human histone deacetylase (HDAC). These compounds were potent enzyme inhibitors, having IC(50)s < 400 nM in a partially purified enzyme assay. However, potency in cell growth inhibition assays ranged over 2 orders of magnitude in two human carcinoma cell lines. Selected compounds having cellular IC50 < 750 nM were tested for maximum tolerated dose (MTD) and for efficacy in the HCT116 human colon tumor xenograft assay. Four compounds having an MTD 100 mg/kg were selected for dose-response studies in the HCT116 xenograft model. One compound, 9 (NVP-LAQ824), had significant dose-related activity in the HCT116 colon and A549 lung tumor models, high MTD, and low gross toxicity. On the basis, in part, of these properties, 9 has entered human clinical trials in 2002.

  DOI：

  10.1021/jm030235w
• 作为产物：
  描述：

  (2E)-3-[4-[[[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenoic acid methyl ester 在 sodium hydroxide 、 羟胺 作用下， 以 甲醇 为溶剂， 以96%的产率得到N-hydroxy-3-[4-[[[2-(1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide
  参考文献：
  名称：

  N-Hydroxy-3-phenyl-2-propenamides as Novel Inhibitors of Human Histone Deacetylase with in Vivo Antitumor Activity:  Discovery of (2E)-N-Hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide (NVP-LAQ824)

  摘要：

  A series of N-hydroxy-3-phenyl-2-propenamides were prepared as novel inhibitors of human histone deacetylase (HDAC). These compounds were potent enzyme inhibitors, having IC(50)s < 400 nM in a partially purified enzyme assay. However, potency in cell growth inhibition assays ranged over 2 orders of magnitude in two human carcinoma cell lines. Selected compounds having cellular IC50 < 750 nM were tested for maximum tolerated dose (MTD) and for efficacy in the HCT116 human colon tumor xenograft assay. Four compounds having an MTD 100 mg/kg were selected for dose-response studies in the HCT116 xenograft model. One compound, 9 (NVP-LAQ824), had significant dose-related activity in the HCT116 colon and A549 lung tumor models, high MTD, and low gross toxicity. On the basis, in part, of these properties, 9 has entered human clinical trials in 2002.

  DOI：

  10.1021/jm030235w

文献信息

• Deacetylase inhibitors
  申请人：——

  公开号：US20030018062A1

  公开（公告）日：2003-01-23

  The present invention provides hydroxamate compounds which are deacetylase inhibitors. The compounds are suitable for pharmaceutical compositions having anti-proliferative properties.

  本发明提供了羟肟酸酯化合物，这些化合物是脱乙酰酶抑制剂。这些化合物适用于具有抗增殖特性的药物组合物。
• [EN] DEACETYLASE INHIBITORS<br/>[FR] INHIBITEURS DE DESACETYLASE
  申请人：NOVARTIS AG

  公开号：WO2002022577A2

  公开（公告）日：2002-03-21

  The present invention provides hydroxamate compounds of formula (I) which are deacetylase inhibitors. The compounds are suitable for pharmaceutical compositions having anti-proliferative properties.

  本发明提供了式（I）的羟肟酸化合物，这些化合物是去乙酰化酶抑制剂。这些化合物适用于具有抗增殖性质的药物组合物。
• [EN] CYCLOOXYGENASE-2 INHIBITOR/HISTONE DEACETYLASE INHIBITOR COMBINATION<br/>[FR] COMBINAISON D'INHIBITEUR DE CYCLOOXIGENASE-2 /INHIBITEUR D'HISTONE DESACETYLASE
  申请人：NOVARTIS AG

  公开号：WO2003039599A1

  公开（公告）日：2003-05-15

  The invention relates to a combination which comprises (a) a cyclooxygenase-2 inhibitor ('COX-2 inhibitor') and (b) a histone deacetylase inhibitor ('HDAI') for simultaneous, concurrent, separate or sequential use, especially for use in the treatment of pre-malignant colon lesions or a colon cancer or other malignancies in a mammal, particularly a human. The invention also relates to pharmaceutical compositions comprising such a combination and to a method of treating pre-malignant colon lesions (e.g.polyps)and colon cancer, as well as other malignancies, in a mammal, particularly a human, with such a combination. The present invention further also relates to a commercial package or product comprising such a combination.

  本发明涉及一种组合物，包括（a）环氧合酶-2抑制剂（“COX-2抑制剂”）和（b）组蛋白去乙酰化酶抑制剂（“HDAI”），用于同时、并行、分离或顺序使用，特别是用于治疗哺乳动物，尤其是人类的癌前结肠病变或结肠癌或其他恶性肿瘤。本发明还涉及包含这种组合物的制药组合物，以及使用这种组合物治疗癌前结肠病变（例如息肉）和结肠癌以及其他恶性肿瘤的方法，特别是在哺乳动物，尤其是人类中使用。本发明还涉及包含这种组合物的商业包装或产品。
• Method for screening for compounds having hdac inhibitory activity
  申请人：Asselbergs Maria Fredericus Alphonsus

  公开号：US20050118596A1

  公开（公告）日：2005-06-02

  The invention relates to the use of Fra-1 levels as a marker for HDAC inhibition. Also disclosed are in vivo and in vitro methods for screening a compound for HDAC inhibitory activity, as well as methods for monitoring the therapeutic efficacy of an HDAC inhibitor in a subject in vivo and for determining resistance to an HDAC inhibitor in vitro or in vivo.

  本发明涉及使用Fra-1水平作为HDAC抑制剂的标记。还揭示了一种用于筛选具有HDAC抑制活性的化合物的体内和体外方法，以及用于监测体内HDAC抑制剂的治疗功效的方法，以及用于确定体外或体内对HDAC抑制剂的耐药性的方法。
• Cyclooxygenase-2 inhibitor/histone deacetylase inhibitor combination
  申请人：Chen Pan Ying-Nan

  公开号：US20050032899A1

  公开（公告）日：2005-02-10

  The invention relates to a combination which comprises (a) a cyclooxygenase-2 inhibitor (“COX-2 inhibitor”) and (b) a histone deacetylase inhibitor (“HDAI”) for simultaneous, concurrent, separate or sequential use, especially for use in the treatment of pre-malignant colon lesions or a colon cancer or other malignancies in a mammal, particularly a human. The invention also relates to pharmaceutical compositions comprising such a combination and to a method of treating pre-malignant colon lesions (e.g. polyps) and colon cancer, as well as other malignancies, in a mammal, particularly a human, with such a combination. The present invention further also relates to a commercial package or product comprising such a combination.

  本发明涉及一种组合物，包括(a)环氧合酶-2抑制剂（“COX-2抑制剂”）和(b)组蛋白去乙酰化酶抑制剂（“HDAI”），用于同时、并行、分离或顺序使用，特别是用于治疗哺乳动物，特别是人类的癌前结肠病变或结肠癌或其他恶性肿瘤。本发明还涉及包括这种组合物的制药组合物以及使用这种组合物治疗癌前结肠病变（例如息肉）和结肠癌以及其他恶性肿瘤的方法，特别是在哺乳动物，特别是人类中。本发明还涉及包含这种组合物的商业包装或产品。