N-(6-(4-isopropylpiperazin-1-yl)pyridin-3-yl)-4-(pyridin-2-yl)benzamide | 1426259-93-9

• 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: N-(6-(4-isopropylpiperazin-1-yl)pyridin-3-yl)-4-(pyridin-2-yl)benzamide
• 英文别名: N-[6-(4-propan-2-ylpiperazin-1-yl)pyridin-3-yl]-4-pyridin-2-ylbenzamide
• CAS: 1426259-93-9
• 化学式: C₂₄H₂₇N₅O
• 分子量: 401.511
• InChiKey: OOMVKCICFUSIFP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  30
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  61.4
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  1-异丙基哌嗪 在 palladium on activated charcoal 、 氢气 、 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 甲醇 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 20.0 ℃ 、101.33 kPa 条件下， 反应 29.0h， 生成 N-(6-(4-isopropylpiperazin-1-yl)pyridin-3-yl)-4-(pyridin-2-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

• 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.
• 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.