ethyl 2-(5-(3-(1H-imidazol-1-yl)propyl)-4-(4-bromophenyl)-6-oxo-3-phenyl-5,6-dihydropyrrolo[3,4-c]pyrazol-1(4H)-yl)acetate | 1542066-81-8

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: ethyl 2-(5-(3-(1H-imidazol-1-yl)propyl)-4-(4-bromophenyl)-6-oxo-3-phenyl-5,6-dihydropyrrolo[3,4-c]pyrazol-1(4H)-yl)acetate
• 英文别名: ethyl 2-(5-(3-(1H-imidazole)propyl)-4-(4-bromophenyl)-6-oxo-3-phenyl-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-yl)acetate；ethyl 2-[4-(4-bromophenyl)-5-(3-imidazol-1-ylpropyl)-6-oxo-3-phenyl-4H-pyrrolo[3,4-c]pyrazol-1-yl]acetate
• CAS: 1542066-81-8
• 化学式: C₂₇H₂₆BrN₅O₃
• 分子量: 548.439
• InChiKey: KTFZDFTVGDXNSA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  36
• 可旋转键数：
  10
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  82.2
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  4-benzoyl-5-(4-bromophenyl)-3-hydroxy-1-[3-(1H-imidazol-1-yl)propyl]-2,5-dihydro-1H-pyrrol-2-one 在 potassium carbonate 、 一水合肼 、 溶剂黄146 作用下， 以 乙醇 为溶剂， 反应 14.25h， 生成 ethyl 2-(5-(3-(1H-imidazol-1-yl)propyl)-4-(4-bromophenyl)-6-oxo-3-phenyl-5,6-dihydropyrrolo[3,4-c]pyrazol-1(4H)-yl)acetate
  参考文献：
  名称：

  Double-Edged Swords as Cancer Therapeutics: Novel, Orally Active, Small Molecules Simultaneously Inhibit p53–MDM2 Interaction and the NF-κB Pathway

  摘要：

  Simultaneous inactivation of p53 and hyperactivation of nuclear factor-kappa B (NF-kappa B) is a common occurrence in human cancer. Currently, antitumor agents are being designed to selectively activate p53 or inhibit NF-kappa B. However, there is no concerted effort yet to deliberately design inhibitors that can simultaneously do both. This paper provided a proof-of-concept study that p53-MDM2 interaction and NF-kappa B pathway can be simultaneously targeted by a small-molecule inhibitor. A series of pyrrolo[3,4-c]pyrazole derivatives were rationally designed and synthesized as the first-in-class inhibitors of p53-MDM2 interaction and NF-kappa B pathway. Most of the compounds were identified to possess nanomolar p53-MDM2 inhibitory activity. Compounds 5q and 5s suppressed NF-kappa B activation through inhibition of I kappa B alpha phosphorylation and elevation of the cytoplasmic levels of p65 and phosphorylated IKK alpha/beta. Biochemical assay for the kinases also supported the fact that pyrrolo[3,4-c]pyrazole compounds directly targeted the NF-kappa B pathway. In addition, four compounds (5j, 5q, 5s, and 5u) effectively inhibited tumor growth in the A549 xenograft model. Further pharmacokinetic study revealed that compound 5q exhibited excellent oral bioavailability (72.9%).

  DOI：

  10.1021/jm401800k

文献信息

• [EN] PYRROLIDONOPYRAZOLE COMPOUNDS AND USE THEREOF AS DRUGS<br/>[FR] COMPOSÉS PYRROLIDONOPYRAZOLES ET LEUR UTILISATION EN TANT QUE MÉDICAMENTS
  申请人：UNIV PLA 2ND MILITARY MEDICAL

  公开号：WO2014134968A1

  公开（公告）日：2014-09-12

  本发明属于医药技术领域。本发明提供了一种吡咯酮类化合物，包括其光学异构体、外消旋体、顺反异构体以及任意组合或其药用盐，结构如式（I）所示。本发明的化合物可作为p53-MDM2/X蛋白相互作用小分子抑制剂。本发明的化合物可用于制备抗肿瘤药物或抗炎药物。
• Double-Edged Swords as Cancer Therapeutics: Novel, Orally Active, Small Molecules Simultaneously Inhibit p53–MDM2 Interaction and the NF-κB Pathway
  作者：Chunlin Zhuang、Zhenyuan Miao、Yuelin Wu、Zizhao Guo、Jin Li、Jianzhong Yao、Chengguo Xing、Chunquan Sheng、Wannian Zhang

  DOI：10.1021/jm401800k

  日期：2014.2.13

  Simultaneous inactivation of p53 and hyperactivation of nuclear factor-kappa B (NF-kappa B) is a common occurrence in human cancer. Currently, antitumor agents are being designed to selectively activate p53 or inhibit NF-kappa B. However, there is no concerted effort yet to deliberately design inhibitors that can simultaneously do both. This paper provided a proof-of-concept study that p53-MDM2 interaction and NF-kappa B pathway can be simultaneously targeted by a small-molecule inhibitor. A series of pyrrolo[3,4-c]pyrazole derivatives were rationally designed and synthesized as the first-in-class inhibitors of p53-MDM2 interaction and NF-kappa B pathway. Most of the compounds were identified to possess nanomolar p53-MDM2 inhibitory activity. Compounds 5q and 5s suppressed NF-kappa B activation through inhibition of I kappa B alpha phosphorylation and elevation of the cytoplasmic levels of p65 and phosphorylated IKK alpha/beta. Biochemical assay for the kinases also supported the fact that pyrrolo[3,4-c]pyrazole compounds directly targeted the NF-kappa B pathway. In addition, four compounds (5j, 5q, 5s, and 5u) effectively inhibited tumor growth in the A549 xenograft model. Further pharmacokinetic study revealed that compound 5q exhibited excellent oral bioavailability (72.9%).