tert-butyl 6-[(thiophen-2-yllsulfonyl)amino]-3-azabicyclo[3.1.0]hexane-3-carboxylate | 1256449-17-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: tert-butyl 6-[(thiophen-2-yllsulfonyl)amino]-3-azabicyclo[3.1.0]hexane-3-carboxylate
• CAS: 1256449-17-8
• 化学式: C₁₄H₂₀N₂O₄S₂
• 分子量: 344.456
• InChiKey: QAVVVCFIQVWCHJ-IAZYJMLFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.89
• 重原子数：
  22.0
• 可旋转键数：
  3.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  75.71
• 氢给体数：
  1.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  tert-butyl 6-[(thiophen-2-yllsulfonyl)amino]-3-azabicyclo[3.1.0]hexane-3-carboxylate 在 盐酸 、 potassium carbonate 作用下， 以 1,4-二氧六环 、 乙腈 为溶剂， 反应 0.5h， 生成 ethyl 2-{6-[(thiophen-2-ylsulfonyl)amino]-3-azabicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxylate
  参考文献：
  名称：

  Discovery of 2-(6-{[(6-Fluoroquinolin-2-yl)methyl]amino}bicyclo[3.1.0]hex-3-yl)-N-hydroxypyrimidine-5-carboxamide (CHR-3996), a Class I Selective Orally Active Histone Deacetylase Inhibitor

  摘要：

  A novel series of HDAC inhibitors demonstrating class I subtype selectivity and good oral bioavailability is described. The compounds are potent enzyme inhibitors (IC50 values less than 100 nM), and improved activity in cell proliferation assays was achieved by modulation of polar surface area (PSA) through the introduction of novel linking groups. Employing oral pharmacokinetic studies in mice, comparing drug levels in spleen to plasma, we selected compounds that were tested for efficacy in human tumor xenograft studies based on their potential to distribute into tumor. One compound, 21r (CHR-3996), showed good oral activity in these models, including dose-related activity in a LoVo xenograft. In addition 21r showed good activity in combination with other anticancer agents in in vitro studies. On the basis of these results, 21r was nominated for clinical development.

  DOI：

  10.1021/jm101177s
• 作为产物：
  描述：

  (1α,5α,6α)-6-Nitro-3-azabicyclo[3.1.0]hexane hydrochloride 在 吡啶 、 4-二甲氨基吡啶 、 10% palladium on activated carbon 、 氢气 、 三乙胺 作用下， 以 乙醇 、 二氯甲烷 为溶剂， 反应 20.0h， 生成 tert-butyl 6-[(thiophen-2-yllsulfonyl)amino]-3-azabicyclo[3.1.0]hexane-3-carboxylate
  参考文献：
  名称：

  Discovery of 2-(6-{[(6-Fluoroquinolin-2-yl)methyl]amino}bicyclo[3.1.0]hex-3-yl)-N-hydroxypyrimidine-5-carboxamide (CHR-3996), a Class I Selective Orally Active Histone Deacetylase Inhibitor

  摘要：

  A novel series of HDAC inhibitors demonstrating class I subtype selectivity and good oral bioavailability is described. The compounds are potent enzyme inhibitors (IC50 values less than 100 nM), and improved activity in cell proliferation assays was achieved by modulation of polar surface area (PSA) through the introduction of novel linking groups. Employing oral pharmacokinetic studies in mice, comparing drug levels in spleen to plasma, we selected compounds that were tested for efficacy in human tumor xenograft studies based on their potential to distribute into tumor. One compound, 21r (CHR-3996), showed good oral activity in these models, including dose-related activity in a LoVo xenograft. In addition 21r showed good activity in combination with other anticancer agents in in vitro studies. On the basis of these results, 21r was nominated for clinical development.

  DOI：

  10.1021/jm101177s