N-(1-isobutoxyethoxy)-2-(6-{[3,5-bis(trifluoromethyl)benzyl]amino}-3-azabicyclo[3.1.0]hex-3-yl)pyrimidine-5-carboxamide | 1256449-58-7

• 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-(1-isobutoxyethoxy)-2-(6-{[3,5-bis(trifluoromethyl)benzyl]amino}-3-azabicyclo[3.1.0]hex-3-yl)pyrimidine-5-carboxamide
• CAS: 1256449-58-7
• 化学式: C₂₅H₂₉F₆N₅O₃
• 分子量: 561.527
• InChiKey: GAYDCGUVVRKIRM-ZLILCNGJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.42
• 重原子数：
  39.0
• 可旋转键数：
  10.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  88.61
• 氢给体数：
  2.0
• 氢受体数：
  7.0

反应信息

• 作为反应物：
  描述：

  N-(1-isobutoxyethoxy)-2-(6-{[3,5-bis(trifluoromethyl)benzyl]amino}-3-azabicyclo[3.1.0]hex-3-yl)pyrimidine-5-carboxamide 、 三氟乙酸 以 甲醇 、 二氯甲烷 为溶剂， 以10%的产率得到N-hydroxy-2-(6-{[3,5-bis(trifluoromethyl)benzyl]amino}-3-azabicyclo[3.1.0]hex-3-yl)pyrimidine-5-carboxamide trifluoroacetate
  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)-3-N-benzyl-6-nitro-2,4-dioxo-3-azabicyclo[3.1.0]hexane 在 盐酸 、 甲醇 、 4-二甲氨基吡啶 、 sodium tetrahydroborate 、 三氟化硼四氢呋喃络合物 、 1-氯乙基氯甲酸酯 、 10% palladium on activated carbon 、 水 、 氢气 、 potassium carbonate 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 sodium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 乙醇 、 二氯甲烷 、 1,2-二氯乙烷 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 77.67h， 生成 N-(1-isobutoxyethoxy)-2-(6-{[3,5-bis(trifluoromethyl)benzyl]amino}-3-azabicyclo[3.1.0]hex-3-yl)pyrimidine-5-carboxamide
  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