N-(4-(4-ethylpiperazin-1-yl)phenyl)-4-(pyridin-4-yl)benzamide | 1440136-46-8

• 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: N-(4-(4-ethylpiperazin-1-yl)phenyl)-4-(pyridin-4-yl)benzamide
• 英文别名: N-[4-(4-ethylpiperazin-1-yl)phenyl]-4-pyridin-4-ylbenzamide
• CAS: 1440136-46-8
• 化学式: C₂₄H₂₆N₄O
• 分子量: 386.497
• InChiKey: RIFLCDPHPIHWOH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  29
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  48.5
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  4-吡啶-4-基苯甲酸 、 4-(4-乙基哌嗪-1-基)苯胺 在 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 12.0h， 以29%的产率得到N-(4-(4-ethylpiperazin-1-yl)phenyl)-4-(pyridin-4-yl)benzamide
  参考文献：
  名称：

  Towards Optimization of Arylamides As Novel, Potent, and Brain-Penetrant Antiprion Lead Compounds

  摘要：

  The prion diseases caused by PrPSc, in alternatively folded form of the cellular prion protein (PrPC), are rapidly progressive, fatal, and untreatable neurodegenerative disorders. We employed HTS ELISA assays to identify compounds that lower the level of PrPSc in prion-infected mouse neuroblastoma (ScN2a-cl3) cells and identified a series of arylamides. Structure-activity relationship (SAR) studies indicated that small amides with one aromatic or heteroaromatic ring on each side of the amide bond are of modest potency. Of note, benzamide (7), with an EC50 of 2200 nM, was one of only a few arylamide hits with a piperazine group on its aniline moiety. The basic piperazine nitrogen can be protonated at physiologic pH, improving solubility, and therefore, we wanted to exploit this feature in our search for a drug candidate. An SAR campaign resulted in several key analogues, including a set with biaryl groups introduced on the carbonyl side for improved potency. Several of these biaryl analogues have submicromolar potency, with the most potent analogue 17 having an EC50 = 22 nM. More importantly, 17 and several biarylamides (20, 24, 26, and 27) Were able to traverse the blood-brain barrier.(BBB) and displayed excellent drug levels in the brains of mice following oral dosing. These biarylamides, may represent good starting points for further lead optimization for the identification of potential drug candidates for the treatment of priori diseases.

  DOI：

  10.1021/ml300454k

文献信息

• Towards Optimization of Arylamides As Novel, Potent, and Brain-Penetrant Antiprion Lead Compounds
  作者：Zhe Li、Satish Rao、Joel R. Gever、Kartika Widjaja、Stanley B. Prusiner、B. Michael Silber

  DOI：10.1021/ml300454k

  日期：2013.7.11

  The prion diseases caused by PrPSc, in alternatively folded form of the cellular prion protein (PrPC), are rapidly progressive, fatal, and untreatable neurodegenerative disorders. We employed HTS ELISA assays to identify compounds that lower the level of PrPSc in prion-infected mouse neuroblastoma (ScN2a-cl3) cells and identified a series of arylamides. Structure-activity relationship (SAR) studies indicated that small amides with one aromatic or heteroaromatic ring on each side of the amide bond are of modest potency. Of note, benzamide (7), with an EC50 of 2200 nM, was one of only a few arylamide hits with a piperazine group on its aniline moiety. The basic piperazine nitrogen can be protonated at physiologic pH, improving solubility, and therefore, we wanted to exploit this feature in our search for a drug candidate. An SAR campaign resulted in several key analogues, including a set with biaryl groups introduced on the carbonyl side for improved potency. Several of these biaryl analogues have submicromolar potency, with the most potent analogue 17 having an EC50 = 22 nM. More importantly, 17 and several biarylamides (20, 24, 26, and 27) Were able to traverse the blood-brain barrier.(BBB) and displayed excellent drug levels in the brains of mice following oral dosing. These biarylamides, may represent good starting points for further lead optimization for the identification of potential drug candidates for the treatment of priori diseases.