N-ethyl-3-(1-(4-(piperazin-1-yl)phenyl)-5-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1H-pyrazol-3-yl)propanamide | 1333146-26-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: N-ethyl-3-(1-(4-(piperazin-1-yl)phenyl)-5-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1H-pyrazol-3-yl)propanamide
• 英文别名: N-ethyl-3-[1-(4-piperazin-1-ylphenyl)-5-[4-[4-(trifluoromethyl)phenyl]phenyl]pyrazol-3-yl]propanamide
• CAS: 1333146-26-1
• 化学式: C₃₁H₃₂F₃N₅O
• 分子量: 547.623
• InChiKey: JGYQMAQNXPMEBL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  40
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  62.2
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  ethyl 3-(1-(4-nitrophenyl)-5-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1H-pyrazol-3-yl)propanoate 在 palladium on activated charcoal 、 氢气 作用下， 以 甲醇 、 5,5-dimethyl-1,3-cyclohexadiene 、 乙醇 、 乙酸乙酯 为溶剂， 120.0~170.0 ℃ 、482.64 kPa 条件下， 生成 N-ethyl-3-(1-(4-(piperazin-1-yl)phenyl)-5-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1H-pyrazol-3-yl)propanamide
  参考文献：
  名称：

  Identification and Characterization of a Novel Integrin-Linked Kinase Inhibitor

  摘要：

  Integrin-linked kinase (ILK) represents a relevant target for cancer therapy in light of its role in promoting oncogenesis and tumor progression. Through the screening of an in-house focused compound library, we identified N-methyl-3-(1-(4-(piperazin-1-yl)phenyl)-5-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1H-pyrazol-3-yl)propanamide (22) as a novel ILK inhibitor (IC50, 0.6 mu M), which exhibited high in vitro potency against a panel of prostate and breast cancer cell lines (IC50, 1-2.5 mu M), while normal epithelial cells were unaffected. Compound 22 facilitated the dephosphorylation of Akt at Ser-473 and other ILK targets, including glycogen synthase kinase-3 beta and myosin light chain. Moreover, 22 suppressed the expression of the transcription/translation factor YB-1 and its targets HER2 and EGFR in PC-3 cells, which could be rescued by the stable expression of constitutively active ILK. Evidence indicates that 22 induced autophagy and apoptosis, both of which were integral to its antiproliferative activity. Together, this broad spectrum of mechanisms underlies the therapeutic potential of 22 in cancer treatment, which is manifested by its in vivo efficacy as a single oral agent in suppressing PC-3 xenograft tumor growth.

  DOI：

  10.1021/jm2007744

文献信息

• [EN] INTEGRIN-LINKED KINASE INHIBITORS<br/>[FR] INHIBITEURS DE KINASE LIÉE À L'INTÉGRINE
  申请人：UNIV OHIO STATE RES FOUND

  公开号：WO2012071310A1

  公开（公告）日：2012-05-31

  A number of compounds and use of the compounds in a method for treating or preventing cancer in a subject by administering to the subject a pharmaceutical composition including a compound of formula (I) or a pharmaceutically acceptable salt thereof are described. The compounds can also be used to inhibit integrin-linked kinase in a cell, which has an effect on the Akt signaling pathway.

  描述了一种化合物的数量以及在治疗或预防受试者癌症的方法中通过向受试者施用包括式（I）化合物或其药用可接受盐的药物组合物来使用这些化合物。这些化合物还可以用于抑制细胞中的整合素相关激酶，从而影响Akt信号通路。
• INTEGRIN-LINKED KINASE INHIBITORS
  申请人：The Ohio State University Research Foundation

  公开号：EP2642856A1

  公开（公告）日：2013-10-02
• US8658647B2
  申请人：——

  公开号：US8658647B2

  公开（公告）日：2014-02-25
• Identification and Characterization of a Novel Integrin-Linked Kinase Inhibitor
  作者：Su-Lin Lee、En-Chi Hsu、Chih-Chien Chou、Hsiao-Ching Chuang、Li-Yuan Bai、Samuel K. Kulp、Ching-Shih Chen

  DOI：10.1021/jm2007744

  日期：2011.9.22

  Integrin-linked kinase (ILK) represents a relevant target for cancer therapy in light of its role in promoting oncogenesis and tumor progression. Through the screening of an in-house focused compound library, we identified N-methyl-3-(1-(4-(piperazin-1-yl)phenyl)-5-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1H-pyrazol-3-yl)propanamide (22) as a novel ILK inhibitor (IC50, 0.6 mu M), which exhibited high in vitro potency against a panel of prostate and breast cancer cell lines (IC50, 1-2.5 mu M), while normal epithelial cells were unaffected. Compound 22 facilitated the dephosphorylation of Akt at Ser-473 and other ILK targets, including glycogen synthase kinase-3 beta and myosin light chain. Moreover, 22 suppressed the expression of the transcription/translation factor YB-1 and its targets HER2 and EGFR in PC-3 cells, which could be rescued by the stable expression of constitutively active ILK. Evidence indicates that 22 induced autophagy and apoptosis, both of which were integral to its antiproliferative activity. Together, this broad spectrum of mechanisms underlies the therapeutic potential of 22 in cancer treatment, which is manifested by its in vivo efficacy as a single oral agent in suppressing PC-3 xenograft tumor growth.