1-((3S)-1-(1-(4-bromo-2,3-difluorophenyl)-3-methylbutyl)piperidin-3-yl)-5-methylpyrimidine-2,4(1H,3H)-dione | 1612223-72-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 1-((3S)-1-(1-(4-bromo-2,3-difluorophenyl)-3-methylbutyl)piperidin-3-yl)-5-methylpyrimidine-2,4(1H,3H)-dione
• 英文别名: 1-[(3S)-1-[1-(4-bromo-2,3-difluorophenyl)-3-methylbutyl]piperidin-3-yl]-5-methylpyrimidine-2,4-dione
• CAS: 1612223-72-9
• 化学式: C₂₁H₂₆BrF₂N₃O₂
• 分子量: 470.357
• InChiKey: BDDVOXOMZAQSQH-MBIQTGHCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  29
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  52.6
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  1-((3S)-1-(1-(4-bromo-2,3-difluorophenyl)-3-methylbutyl)piperidin-3-yl)-5-methylpyrimidine-2,4(1H,3H)-dione 在 N-甲基吡咯烷酮 、 四(三苯基膦)钯 、 potassium carbonate 作用下， 以 乙腈 为溶剂， 反应 2.0h， 生成 2-(3-chlorophenoxy)-3-fluoro-4-(3-methyl-1-((S)-3-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)piperidin-1-yl)butyl)benzonitrile
  参考文献：
  名称：

  Antibacterial Inhibitors of Gram-Positive Thymidylate Kinase: Structure–Activity Relationships and Chiral Preference of a New Hydrophobic Binding Region

  摘要：

  Thymidylate kinase (TMK), an essential enzyme in bacterial DNA biosynthesis, is an attractive therapeutic target for the development of novel antibacterial agents, and we continue to explore TMK inhibitors with improved potency, protein binding, and pharmacokinetic potential. A structure-guided design approach was employed to exploit a previously unexplored region in Staphylococcus aureus TMK via novel interactions. These efforts produced compound 39, with 3 nM IC50 against S. aureus TMK and 2 mu g/mL MIC against methicillin-resistant S. aureus (MRSA). This compound exhibits a striking inverted chiral preference for binding relative to earlier compounds and also has improved physical properties and pharmacokinetics over previously published compounds. An example of this new series was efficacious in a murine S. aureus infection model, suggesting that compounds like 39 are options for further work toward a new Gram-positive antibiotic by maintaining a balance of microbiological potency, low clearance, and low protein binding that can result in lower efficacious doses.

  DOI：

  10.1021/jm500463c
• 作为产物：
  描述：

  1,4-二溴-2,3-二氟苯 在 isopropylmagnesium chloride, lithium chloride complex 、 三乙胺 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 、 乙腈 为溶剂， 反应 44.0h， 生成 1-((3S)-1-(1-(4-bromo-2,3-difluorophenyl)-3-methylbutyl)piperidin-3-yl)-5-methylpyrimidine-2,4(1H,3H)-dione
  参考文献：
  名称：

  Antibacterial Inhibitors of Gram-Positive Thymidylate Kinase: Structure–Activity Relationships and Chiral Preference of a New Hydrophobic Binding Region

  摘要：

  Thymidylate kinase (TMK), an essential enzyme in bacterial DNA biosynthesis, is an attractive therapeutic target for the development of novel antibacterial agents, and we continue to explore TMK inhibitors with improved potency, protein binding, and pharmacokinetic potential. A structure-guided design approach was employed to exploit a previously unexplored region in Staphylococcus aureus TMK via novel interactions. These efforts produced compound 39, with 3 nM IC50 against S. aureus TMK and 2 mu g/mL MIC against methicillin-resistant S. aureus (MRSA). This compound exhibits a striking inverted chiral preference for binding relative to earlier compounds and also has improved physical properties and pharmacokinetics over previously published compounds. An example of this new series was efficacious in a murine S. aureus infection model, suggesting that compounds like 39 are options for further work toward a new Gram-positive antibiotic by maintaining a balance of microbiological potency, low clearance, and low protein binding that can result in lower efficacious doses.

  DOI：

  10.1021/jm500463c