2-(4-(4-((6-fluoropyridin-3-yl)methyl)piperazin-1-yl)phenyl)benzo[d]oxazole | 1426259-89-3

• 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: 2-(4-(4-((6-fluoropyridin-3-yl)methyl)piperazin-1-yl)phenyl)benzo[d]oxazole
• 英文别名: 2-[4-[4-[(6-Fluoropyridin-3-yl)methyl]piperazin-1-yl]phenyl]-1,3-benzoxazole；2-[4-[4-[(6-fluoropyridin-3-yl)methyl]piperazin-1-yl]phenyl]-1,3-benzoxazole
• CAS: 1426259-89-3
• 化学式: C₂₃H₂₁FN₄O
• 分子量: 388.444
• InChiKey: VQIPFMOEPPWFRZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  45.4
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  1-BOC-4-(4-甲酰苯基)哌嗪 在 甲酸 、 2,2,6,6-四甲基哌啶氧化物 、 氧气 、 三氟乙酸 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 18.0h， 生成 2-(4-(4-((6-fluoropyridin-3-yl)methyl)piperazin-1-yl)phenyl)benzo[d]oxazole
  参考文献：
  名称：

  Discovery and Preliminary Structure–Activity Relationship of Arylpiperazines as Novel, Brain-Penetrant Antiprion Compounds

  摘要：

  Creutzfeldt-Jakob disease and kuru in humans, BSE in cattle, and scrapie in sheep are fatal neurodegenerative disorders. Such illnesses are caused by the conversion and accumulation of a misfolded pathogenic isoform (termed PrPSc) of a normally benign, host cellular protein, denoted PrPC. We employed high-throughput screening enzyme-linked immunosorbent assays to evaluate compounds for their ability to reduce the level of PrPSc in Rocky Mountain Laboratory prion-infected mouse neuroblastoma cells (ScN2a-cl3). Arylpiperazines were among the active compounds identified, but the initial hits suffered from low potency and poor drug-likeness. The best of those hits, such as 1, 7, 13, and 19, displayed moderate antiprion activity with EC50 values in the micromolar range. Key analogues were designed and synthesized on the basis of the structure-activity relationship, with analogues 41, 44, 46, and 47 found to have submicromolar potency. Analogues 41 and 44 were able to penetrate the blood-brain barrier and achieved excellent drug concentrations in the brains of mice after oral dosing. These compounds represent good starting points for further lead optimization in our pursuit of potential drug candidates for the treatment of prion diseases.

  DOI：

  10.1021/ml300472n

文献信息

• NOVEL ANTIPRION COMPOUNDS
  申请人：The Regents of the University of California

  公开号：US20140329863A1

  公开（公告）日：2014-11-06

  Described herein are novel compositions and methods of treatment addressing diseases such as neurodegenerative diseases, including prion diseases and Alzheimer's disease.

  本文描述了一种新的组合物和治疗方法，用于治疗神经退行性疾病，包括朊病和阿尔茨海默病。
• [EN] NOVEL ANTIPRION COMPOUNDS<br/>[FR] NOUVEAUX COMPOSÉS D'ANTIPRION
  申请人：UNIV CALIFORNIA

  公开号：WO2013033037A2

  公开（公告）日：2013-03-07

  Described herein are novel compositions and methods of treatment addressing diseases such as neurodegenerative diseases, including prion diseases and Alzheimer's disease.
• Discovery and Preliminary Structure–Activity Relationship of Arylpiperazines as Novel, Brain-Penetrant Antiprion Compounds
  作者：Zhe Li、Joel R. Gever、Satish Rao、Kartika Widjaja、Stanley B. Prusiner、B. Michael Silber

  DOI：10.1021/ml300472n

  日期：2013.4.11

  Creutzfeldt-Jakob disease and kuru in humans, BSE in cattle, and scrapie in sheep are fatal neurodegenerative disorders. Such illnesses are caused by the conversion and accumulation of a misfolded pathogenic isoform (termed PrPSc) of a normally benign, host cellular protein, denoted PrPC. We employed high-throughput screening enzyme-linked immunosorbent assays to evaluate compounds for their ability to reduce the level of PrPSc in Rocky Mountain Laboratory prion-infected mouse neuroblastoma cells (ScN2a-cl3). Arylpiperazines were among the active compounds identified, but the initial hits suffered from low potency and poor drug-likeness. The best of those hits, such as 1, 7, 13, and 19, displayed moderate antiprion activity with EC50 values in the micromolar range. Key analogues were designed and synthesized on the basis of the structure-activity relationship, with analogues 41, 44, 46, and 47 found to have submicromolar potency. Analogues 41 and 44 were able to penetrate the blood-brain barrier and achieved excellent drug concentrations in the brains of mice after oral dosing. These compounds represent good starting points for further lead optimization in our pursuit of potential drug candidates for the treatment of prion diseases.