4-benzoyl-5-(4-bromophenyl)-1-[3-(1H-imidazol-1-yl)propyl]-3-(propan-2-yloxy)-2,5-dihydro-1H-pyrrol-2-one | 1391501-92-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯啉
• 英文名称: 4-benzoyl-5-(4-bromophenyl)-1-[3-(1H-imidazol-1-yl)propyl]-3-(propan-2-yloxy)-2,5-dihydro-1H-pyrrol-2-one
• 英文别名: 3-benzoyl-2-(4-bromophenyl)-1-(3-imidazol-1-ylpropyl)-4-propan-2-yloxy-2H-pyrrol-5-one
• CAS: 1391501-92-0
• 化学式: C₂₆H₂₆BrN₃O₃
• 分子量: 508.415
• InChiKey: NRGBWBGUOGGUIL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  33
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  64.4
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  1-(3-氨基丙基)咪唑 在 偶氮二甲酸二异丙酯 、 三苯基膦 作用下， 以 四氢呋喃 、 1,4-二氧六环 为溶剂， 反应 24.5h， 生成 4-benzoyl-5-(4-bromophenyl)-1-[3-(1H-imidazol-1-yl)propyl]-3-(propan-2-yloxy)-2,5-dihydro-1H-pyrrol-2-one
  参考文献：
  名称：

  Discovery, Synthesis, and Biological Evaluation of Orally Active Pyrrolidone Derivatives as Novel Inhibitors of p53–MDM2 Protein–Protein Interaction

  摘要：

  The p53-MDM2 interaction has been proved to,, be a valuable target, to develop effective antitumor agents. Novel p53-MDM2 inhibitors bearing pyrrolidone scaffolds were successfully identified by structure-based design. The nanomolar inhibitor 5 possessed good p53-MDM2 inhibitory activity (K-i = 780 nM) due to its hydrophobic and hydrogen bonding interactions with MDM2. Further hit optimization led to. the discovery of a number of highly potent pyrrolidone derivative's with improved p537-MDM2 inhibitory activity and in vitro antiproliferative potency. Compounds 41 (K-i = 260.0 nM) and 60a (K-i = 150.0 nM) showed good and selective activity against tumor cells with deleted p53. In addition, these two Compounds also :effectively inhibited the tumor growth in the A549 xenograft model: Interestingly, compound 41 was proved to be a potent MDM2/MDMX dual inhibitor. The novel pyrrolidone p53-MDM2 inhibitors represent promising lead structures for the development Of novel antitumor agents.

  DOI：

  10.1021/jm300969t

文献信息

• [EN] BIOMARKERS FOR CANCER THERAPY USING MDM2 ANTAGONISTS<br/>[FR] BIOMARQUEURS POUR THÉRAPIE ANTICANCÉREUSE UTILISANT DES ANTAGONISTES DE MDM2
  申请人：OTSUKA PHARMA CO LTD

  公开号：WO2021130682A2

  公开（公告）日：2021-07-01

  [EN] The invention provides biomarkers to predict effective treatment of cancer using an MDM2 antagonist. Identifying one or more of these biomarkers in a cancer patient allows a determination to be made whether the patient's cancer is likely to be successfully treated using an MDM2 antagonist. Accordingly, the invention relates generally to a companion diagnostic for MDM2 antagonist therapy. The biomarkers are: (i) BAP1; and/or (ii) CDKN2A; and/or (iii) one, two, three, four, five, six, seven, eight, nine, ten or more of: CXCL10, CXCL11, RSAD2, MX1, BATF2, IFI44L, IFITM1, ISG15, CMPK2, IFI27, CD74, IFIH1, CCRL2, IFI44, HERC6, ISG20, IFIT3, HLA-C, OAS1, IFI35, IRF9, EPSTI1, USP18, BST2, CSF1, C1S, DHX58, TRIM14, OASL, IRF7, LGALS3BP, DDX60, LAP3, LAMP3, PARP12, PARP9, SP110, PLSCR1, WARS, STAT1, IRF3, IRF5, MSC, JUN, SPI1, IRF1, COMMD3-BMI1, STAT2, RUNX3, SREBF1, FLI1 and BRCA1.
  [FR] L'invention concerne des biomarqueurs pour prédire un traitement efficace du cancer utilisant un antagoniste de MDM2. L'identification d'un ou de plusieurs de ces biomarqueurs chez un patient cancéreux permet de déterminer si le cancer du patient est susceptible d'être traité avec succès au moyen d'un antagoniste de MDM2. En conséquence, l'invention concerne de manière générale un diagnostic compagnon pour une thérapie par antagoniste de MDM2. Les biomarqueurs sont : (I) BAP1 ; et/ou (ii) CDKN2A ; et/ou (iii) un, deux, trois, quatre, cinq, six, sept, huit, neuf, dix ou plus parmi : CXCL10, CXCL11, RSAD2, MX1, BATF2, IFI44L, IFITM1, ISG15, CMPK2, IFI27, CD74, IFIH1, CCRL2, IFI44, HERC6, ISG20, IFIT3, HLA-C, OAS1, IFI35, IRF9, EPSTI1, USP18, BST2, CSF1, C1S, DHX58, TRIM14, OASL, IRF7, LGALS3BP, DDX60, LAP3, LAMP3, PARP12, PARP9, SP110, PLSCR1, WARS, STAT1, IRF3, IRF5, MSC, JUN, SPI1, IRF1, COMMD3-BMI1, STAT2, RUNX3, SREBF1, FLI1 et BRCA1.
• [EN] BIOMARKERS FOR CANCER THERAPY USING MDM2 ANTAGONISTS<br/>[FR] BIOMARQUEURS POUR LA THÉRAPIE ANTICANCÉREUSE UTILISANT DES ANTAGONISTES DE MDM2
  申请人：[en]OTSUKA PHARMACEUTICAL CO., LTD.

  公开号：WO2022185260A1

  公开（公告）日：2022-09-09

  The invention provides DNA damage response (DDR) pathway genes and their gene products as biomarkers to predict effective treatment of cancer using an MDM2 antagonist. Identifying one or more DDR pathway biomarkers in a cancer patient allows a determination to be made whether the patient's cancer is likely to be successfully treated using an MDM2 antagonist. Accordingly, the invention relates generally to a companion diagnostic for MDM2 antagonist therapy. In particular, the DDR pathway comprises one or more genes from: the homologous recombination repair (HRR) pathway; the non-homologous end joining (NHEJ) pathway; the mismatch repair (MMR) pathway; the Fanconi Anemia (FA) pathway; and/or the base excision repair (BER) pathway.
• Discovery, Synthesis, and Biological Evaluation of Orally Active Pyrrolidone Derivatives as Novel Inhibitors of p53–MDM2 Protein–Protein Interaction
  作者：Chunlin Zhuang、Zhenyuan Miao、Lingjian Zhu、Guoqiang Dong、Zizhao Guo、Shengzheng Wang、Yongqiang Zhang、Yuelin Wu、Jianzhong Yao、Chunquan Sheng、Wannian Zhang

  DOI：10.1021/jm300969t

  日期：2012.11.26

  The p53-MDM2 interaction has been proved to,, be a valuable target, to develop effective antitumor agents. Novel p53-MDM2 inhibitors bearing pyrrolidone scaffolds were successfully identified by structure-based design. The nanomolar inhibitor 5 possessed good p53-MDM2 inhibitory activity (K-i = 780 nM) due to its hydrophobic and hydrogen bonding interactions with MDM2. Further hit optimization led to. the discovery of a number of highly potent pyrrolidone derivative's with improved p537-MDM2 inhibitory activity and in vitro antiproliferative potency. Compounds 41 (K-i = 260.0 nM) and 60a (K-i = 150.0 nM) showed good and selective activity against tumor cells with deleted p53. In addition, these two Compounds also :effectively inhibited the tumor growth in the A549 xenograft model: Interestingly, compound 41 was proved to be a potent MDM2/MDMX dual inhibitor. The novel pyrrolidone p53-MDM2 inhibitors represent promising lead structures for the development Of novel antitumor agents.