2-(3-chlorophenoxy)-3-methoxy-4-{1-[(3S)-3-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)piperidin-1-yl]propyl}benzoic acid | 1612223-69-4

• 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: 2-(3-chlorophenoxy)-3-methoxy-4-{1-[(3S)-3-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)piperidin-1-yl]propyl}benzoic acid
• 英文别名: 2-(3-chlorophenoxy)-3-methoxy-4-[1-[(3S)-3-(5-methyl-2,4-dioxopyrimidin-1-yl)piperidin-1-yl]propyl]benzoic acid
• CAS: 1612223-69-4
• 化学式: C₂₇H₃₀ClN₃O₆
• 分子量: 528.005
• InChiKey: LWVFVEIAPUMILP-HXBUSHRASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  37
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  108
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  2-(3-chlorophenoxy)-3-methoxy-4-{1-[(3S)-3-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)piperidin-1-yl]propyl}benzoic acid 在 二乙胺 作用下， 以 甲醇 、 乙醇 、 正己烷 为溶剂， 以30%的产率得到2-(3-chlorophenoxy)-3-methoxy-4-{(1R)-1-[(3S)-3-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)piperidin-1-yl]propyl}benzoic acid
  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-[(3S)-1-{1-[4-bromo-3-(3-chlorophenoxy)-2-methoxyphenyl]propyl}piperidin-3-yl]-5-methylpyrimidine-2,4(1H,3H)-dione 在 四(三苯基膦)钯 、 sodium hydroxide 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 12.75h， 生成 2-(3-chlorophenoxy)-3-methoxy-4-{1-[(3S)-3-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)piperidin-1-yl]propyl}benzoic acid
  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