1,3-diphenethyl-1,3-diazepane-2,4,7-trione | 1276033-18-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂卓
• 英文名称: 1,3-diphenethyl-1,3-diazepane-2,4,7-trione
• 英文别名: 1,3-Bis(2-phenylethyl)-1,3-diazepane-2,4,7-trione
• CAS: 1276033-18-1
• 化学式: C₂₁H₂₂N₂O₃
• 分子量: 350.417
• InChiKey: KUKUXFCXSKUEDU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  26
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  57.7
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  2-苯乙胺 在 三乙胺 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 34.0h， 生成 1,3-diphenethyl-1,3-diazepane-2,4,7-trione
  参考文献：
  名称：

  Pyrimidine-2,4,6-trione Derivatives and Their Inhibition of Mutant SOD1-Dependent Protein Aggregation. Toward a Treatment for Amyotrophic Lateral Sclerosis

  摘要：

  Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons, leading to muscle weakness, paralysis, and death, most often from respiratory failure. The only FDA-approved drug for the treatment of ALS, riluzole, only extends the median survival in patients by 2-3 months. There is an urgent need for novel therapeutic strategies for this devastating disease. Using a high-throughput screening assay targeting an ALS cultured cell model (PC12-G93A-YFP cell line), we previously identified three chemotypes that were neuroprotective. We present a further detailed analysis of one promising scaffold from that group, pyrimidine-2,4,6-triones (PYTs), characterizing a number of PYT analogues using SAR and ADME. The PYT compounds show good potency, superior ADME data, low toxicity, brain penetration, and excellent oral bioavailability. Compounds from this series show 100% efficacy in the protection assay with a good correlation in activity between the protection and protein aggregation assays. The modifications of the PYT scaffold presented here suggest that this chemical structure may be a novel drug candidate scaffold for use in clinical trials in ALS.

  DOI：

  10.1021/jm101549k

文献信息

• Pyrimidine-2,4,6-trione Derivatives and Their Inhibition of Mutant SOD1-Dependent Protein Aggregation. Toward a Treatment for Amyotrophic Lateral Sclerosis
  作者：Guoyao Xia、Radhia Benmohamed、Jinho Kim、Anthony C. Arvanites、Richard I. Morimoto、Robert J. Ferrante、Donald R. Kirsch、Richard B. Silverman

  DOI：10.1021/jm101549k

  日期：2011.4.14

  Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons, leading to muscle weakness, paralysis, and death, most often from respiratory failure. The only FDA-approved drug for the treatment of ALS, riluzole, only extends the median survival in patients by 2-3 months. There is an urgent need for novel therapeutic strategies for this devastating disease. Using a high-throughput screening assay targeting an ALS cultured cell model (PC12-G93A-YFP cell line), we previously identified three chemotypes that were neuroprotective. We present a further detailed analysis of one promising scaffold from that group, pyrimidine-2,4,6-triones (PYTs), characterizing a number of PYT analogues using SAR and ADME. The PYT compounds show good potency, superior ADME data, low toxicity, brain penetration, and excellent oral bioavailability. Compounds from this series show 100% efficacy in the protection assay with a good correlation in activity between the protection and protein aggregation assays. The modifications of the PYT scaffold presented here suggest that this chemical structure may be a novel drug candidate scaffold for use in clinical trials in ALS.