3-(3-(cyclohexyl(methyl)amino)propyl)-8-methoxy-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one | 891016-35-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯并嘧啶类
• 英文名称: 3-(3-(cyclohexyl(methyl)amino)propyl)-8-methoxy-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one
• 英文别名: 3-{3-[cyclohexyl(methyl)amino]propyl}-8-methoxy-3H,4H,5H-pyrimido[5,4-b]indol-4-one；3-[3-[cyclohexyl(methyl)amino]propyl]-8-methoxy-5H-pyrimido[5,4-b]indol-4-one
• CAS: 891016-35-6
• 化学式: C₂₁H₂₈N₄O₂
• 分子量: 368.479
• InChiKey: ZZYFLPWOLNEUGF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  27
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  60.9
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  3-氨基-5-甲氧基-1H-吲哚-2-羧酸乙酯 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 12.0h， 生成 3-(3-(cyclohexyl(methyl)amino)propyl)-8-methoxy-3,5-dihydro-4H-pyrimido[5,4-b]indol-4-one
  参考文献：
  名称：

  Design, Optimization, and Study of Small Molecules That Target Tau Pre-mRNA and Affect Splicing

  摘要：

  Approximately 95% of human genes are alternatively spliced, and aberrant splicing events can cause disease. One pre-mRNA that is alternatively spliced and linked to neurodegenerative diseases is tau (microtubule-associated protein tau), which can cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) and can contribute to Alzheimer's disease. Here, we describe the design of structure-specific lead small molecules that directly target tau pre-mRNA from sequence. This was followed by hit expansion and analogue synthesis to further improve upon these initial lead molecules. The emergent compounds were assessed for functional activity in a battery of assays, including binding assays and an assay that mimics molecular recognition of tau pre-mRNA by a U1 small nuclear ribonucleoprotein (snRNP) splicing factor. Compounds that emerged from these studies had enhanced potency and selectivity for the target RNA relative to the initial hits, while also having significantly improved drug-like properties. The compounds are shown to directly target tau pre-mRNA in cells, via chemical cross-linking and isolation by pull-down target profiling, and to rescue disease-relevant splicing of tau pre-mRNA in a variety of cellular systems, including primary neurons. More broadly, this study shows that lead, structure-specific compounds can be designed from sequence and then further optimized for their physicochemical properties while at the same time enhancing their activity.

  DOI：

  10.1021/jacs.0c00768