3-(1-(4-aminophenyl)-5-(4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-1H-pyrazol-3-yl)-N-methylpropanamide | 1333147-03-7

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 3-(1-(4-aminophenyl)-5-(4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-1H-pyrazol-3-yl)-N-methylpropanamide
• 英文别名: 3-(1-(4-aminophenyl)-5-[4'-(trifluoromethyl)-(1,1'-biphenyl)-4-yl]-1H-pyrazol-3-yl)-N-methyl-propanamide；3-[1-(4-aminophenyl)-5-[4-[4-(trifluoromethyl)phenyl]phenyl]pyrazol-3-yl]-N-methylpropanamide
• CAS: 1333147-03-7
• 化学式: C₂₆H₂₃F₃N₄O
• 分子量: 464.49
• InChiKey: CJBQRBYTOIQSFW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  34
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  72.9
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  3-(1-(4-aminophenyl)-5-(4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-1H-pyrazol-3-yl)-N-methylpropanamide 在 盐酸 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 生成 3-amino-N-(4-(3-(3-(methylamino)-3-oxopropyl)-5-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1H-pyrazol-1-yl)phenyl)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
• 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 、 乙醇 、 乙酸乙酯 为溶剂， 120.0 ℃ 、482.64 kPa 条件下， 反应 28.0h， 生成 3-(1-(4-aminophenyl)-5-(4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-1H-pyrazol-3-yl)-N-methylpropanamide
  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。
• AMIDE INHIBITORS OF RENIN
  申请人：Gant Thomas G.

  公开号：US20100124550A1

  公开（公告）日：2010-05-20

  The present invention relates to new amide inhibitors of renin, pharmaceutical compositions thereof, and methods of use thereof

  本发明涉及新的肾素酶抑制剂酰胺、其药物组成以及使用方法。
• Irreversible inhibitors of pyruvate kinase M2 and the use thereof
  申请人：China Medical University

  公开号：US20210221801A1

  公开（公告）日：2021-07-22

  The invention provides a novel class of propiolylamide-based irreversible inhibitors of PKM2 compounds of the general formula I, pharmaceutical compositions, and methods of inducing an anti-tumor effect in a subject suffering from tumor comprising administering to the subject a pharmaceutical composition comprising an effective amount of compound of formula I.

  这项发明提供了一类新型的基于丙炔酰胺的PKM2不可逆抑制剂化合物，其一般化学式为I，以及诱导受患肿瘤的对象产生抗肿瘤效果的方法，包括向该对象投与包含化合物I有效量的药物组合物的药物组合物。
• Development of Novel Irreversible Pyruvate Kinase M2 Inhibitors
  作者：I-Shan Hsieh、Balraj Gopula、Chi-Chi Chou、Hsiang-Yi Wu、Geen-Dong Chang、Wen-Jin Wu、Chih-Shiang Chang、Po-Chen Chu、Ching S. Chen

  DOI：10.1021/acs.jmedchem.9b00763

  日期：2019.9.26

  As cancer cells undergo metabolic reprogramming in the course of tumorigenesis, targeting energy metabolism represents a promising strategy in cancer therapy. Among various metabolic enzymes examined, pyruvate kinase M2 type (PKM2) has received much attention in light of its multifaceted function in promoting tumor growth and progression. In this study, we reported the development of a novel irreversible inhibitor of PKM2, compound 1, that exhibits a differential tumor-suppressive effect among an array of cancer cell lines. We further used a clickable activity-based protein profiling (ABPP) probe and SILAC coupled with LC-MS/MS to identify the Cys-317 and Cys-326 residues of PKM2 as the covalent binding sites. Equally important, compound 1 at 10 mg/kg was effective in suppressing xenograft tumor growth in nude mice without causing acute toxicity by targeting both metabolic and oncogenic functions. Together, these data suggest its translational potential to foster new strategies for cancer therapy.
• ANTIBACTERIAL PROTEIN KINASE INHIBITORS
  申请人：The Ohio State University

  公开号：EP2879679A2

  公开（公告）日：2015-06-10