(S)-3-(2-isocyanato-3,3-dimethylbutyl)-1-methyldihydropyrimidine-2,4(1H,3H)-dione | 1217350-93-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 英文名称: (S)-3-(2-isocyanato-3,3-dimethylbutyl)-1-methyldihydropyrimidine-2,4(1H,3H)-dione
• CAS: 1217350-93-0
• 化学式: C₁₂H₁₉N₃O₃
• 分子量: 253.301
• InChiKey: BVVBAPGCVJXBLA-SECBINFHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.02
• 重原子数：
  18.0
• 可旋转键数：
  3.0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  70.05
• 氢给体数：
  0.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  methyl (1R,2S,5S)-3-((S)-2-amino-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate 、 (S)-3-(2-isocyanato-3,3-dimethylbutyl)-1-methyldihydropyrimidine-2,4(1H,3H)-dione 在 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 为溶剂， 生成
  参考文献：
  名称：

  Second-Generation Highly Potent and Selective Inhibitors of the Hepatitis C Virus NS3 Serine Protease

  摘要：

  The hepatitis C virus (HCV) infection is a leading cause of chronic liver disease. The moderate efficacy along with side effects of the current pegylated interferon and ribavirin combination therapy underscores the need for more effective and safer new treatment. In an effort to improve upon our current clinical candidate, Boceprevir (SCH 503034), extensive SAR studies were performed on the P3 capping moieties. This led to the discovery of tert-leucinol derived cyclic imides as a potent series of novel P3 capping groups. Thus, the introduction of these imide caps improved the cell-based replicon EC90 by more than 10-fold. A number of imides with various substitutions, ring sizes, bicyclic systems, and heterocyclic rings were explored. The 4,4-dimethyl substituted glutarimide emerged as the best cap as exemplified in compound 21 (K-i* = 4 nM, EC90 = 40 nM). Systematic optimization of different positions (P', P3, and P1) of the inhibitor resulted in the identification of the lead compound 46, which had an excellent potency (K-i* = 4 nM, EC90 = 30 nM) and good pharmacokinetic profile (22% and 35% bioavailability in rats and dogs, respectively). X-ray structure of inhibitor 46 bound to the enzyme revealed that there was an additional hydrogen bonding interaction between one of the imide carbonyls and Cys159.

  DOI：

  10.1021/jm801238q
• 作为产物：
  描述：

  光气 、 在 碳酸氢钠 作用下， 以 二氯甲烷 、 水 为溶剂， 生成 (S)-3-(2-isocyanato-3,3-dimethylbutyl)-1-methyldihydropyrimidine-2,4(1H,3H)-dione
  参考文献：
  名称：

  Second-Generation Highly Potent and Selective Inhibitors of the Hepatitis C Virus NS3 Serine Protease

  摘要：

  The hepatitis C virus (HCV) infection is a leading cause of chronic liver disease. The moderate efficacy along with side effects of the current pegylated interferon and ribavirin combination therapy underscores the need for more effective and safer new treatment. In an effort to improve upon our current clinical candidate, Boceprevir (SCH 503034), extensive SAR studies were performed on the P3 capping moieties. This led to the discovery of tert-leucinol derived cyclic imides as a potent series of novel P3 capping groups. Thus, the introduction of these imide caps improved the cell-based replicon EC90 by more than 10-fold. A number of imides with various substitutions, ring sizes, bicyclic systems, and heterocyclic rings were explored. The 4,4-dimethyl substituted glutarimide emerged as the best cap as exemplified in compound 21 (K-i* = 4 nM, EC90 = 40 nM). Systematic optimization of different positions (P', P3, and P1) of the inhibitor resulted in the identification of the lead compound 46, which had an excellent potency (K-i* = 4 nM, EC90 = 30 nM) and good pharmacokinetic profile (22% and 35% bioavailability in rats and dogs, respectively). X-ray structure of inhibitor 46 bound to the enzyme revealed that there was an additional hydrogen bonding interaction between one of the imide carbonyls and Cys159.

  DOI：

  10.1021/jm801238q