tert-butyl 5-(((4-nitrophenoxy)carbonyloxy)methyl)-1H-imidazole-1-carboxylate | 1401248-97-2

• 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: tert-butyl 5-(((4-nitrophenoxy)carbonyloxy)methyl)-1H-imidazole-1-carboxylate
• 英文别名: Tert-butyl 5-[(4-nitrophenoxy)carbonyloxymethyl]imidazole-1-carboxylate；tert-butyl 5-[(4-nitrophenoxy)carbonyloxymethyl]imidazole-1-carboxylate
• CAS: 1401248-97-2
• 化学式: C₁₆H₁₇N₃O₇
• 分子量: 363.327
• InChiKey: FHPYMMOARAWBKR-UHFFFAOYSA-N

物化性质

• 沸点：
  535.7±60.0 °C(Predicted)
• 密度：
  1.34±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  26
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  126
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (S)-N-((2R,5R)-5-amino-1,6-diphenylhexan-2-yl)-2-(3-((2-isopropylthiazol-4-yl)methyl)-3-methylureido)-3-methylbutanamide hydrochloride 、 tert-butyl 5-(((4-nitrophenoxy)carbonyloxy)methyl)-1H-imidazole-1-carboxylate 在 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 16.0h， 以26 mg的产率得到tert-butyl 5-((5S,8R,11R)-8,11-dibenzyl-5-isopropyl-1-(2-isopropylthiazol-4-yl)-2-methyl -3,6,13-trioxo-14-oxa-2,4,7,12-tetraazapentadecan-15-yl)-1H-imidazole-1-carboxylate
  参考文献：
  名称：

  Pyridine-Substituted Desoxyritonavir Is a More Potent Inhibitor of Cytochrome P450 3A4 than Ritonavir

  摘要：

  Utilization of the cytochrome P450 3A4 (CYP3A4) inhibitor ritonavir as a pharmacoenhancer for anti-HIV drugs revolutionized the treatment of HIV infection. However, owing to ritonavir-related complications, there is a need for development of new CYP3A4 inhibitors with improved pharmacochemical properties, which requires a full understanding of the CYP3A4 inactivation mechanisms and the unraveling of possible inhibitor binding modes. We investigated the mechanism of CYP3A4 interaction with three desoxyritonavir analogues, containing the heme-ligating imidazole, oxazole, or pyridine group instead of the thiazole moiety (compounds 1, 2, and 3, respectively). Our data show that compound 3 is superior to ritonavir in terms of binding affinity and inhibitory potency owing to greater flexibility and the ability to adopt a conformation that minimizes steric clashing and optimizes protein-ligand interactions. Additionally, Ser119 was identified as a key residue assisting binding of ritonavir-like inhibitors, which emphasizes the importance of polar interactions in the CYP3A4-ligand association.

  DOI：

  10.1021/jm400288z
• 作为产物：
  描述：

  二(对硝基苯)碳酸酯 、 1-tert-butoxycarbonyl-4-hydroxymethylimidazole 在 三乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 16.0h， 生成 tert-butyl 5-(((4-nitrophenoxy)carbonyloxy)methyl)-1H-imidazole-1-carboxylate
  参考文献：
  名称：

  Pyridine-Substituted Desoxyritonavir Is a More Potent Inhibitor of Cytochrome P450 3A4 than Ritonavir

  摘要：

  Utilization of the cytochrome P450 3A4 (CYP3A4) inhibitor ritonavir as a pharmacoenhancer for anti-HIV drugs revolutionized the treatment of HIV infection. However, owing to ritonavir-related complications, there is a need for development of new CYP3A4 inhibitors with improved pharmacochemical properties, which requires a full understanding of the CYP3A4 inactivation mechanisms and the unraveling of possible inhibitor binding modes. We investigated the mechanism of CYP3A4 interaction with three desoxyritonavir analogues, containing the heme-ligating imidazole, oxazole, or pyridine group instead of the thiazole moiety (compounds 1, 2, and 3, respectively). Our data show that compound 3 is superior to ritonavir in terms of binding affinity and inhibitory potency owing to greater flexibility and the ability to adopt a conformation that minimizes steric clashing and optimizes protein-ligand interactions. Additionally, Ser119 was identified as a key residue assisting binding of ritonavir-like inhibitors, which emphasizes the importance of polar interactions in the CYP3A4-ligand association.

  DOI：

  10.1021/jm400288z

文献信息

• Pyridine-Substituted Desoxyritonavir Is a More Potent Inhibitor of Cytochrome P450 3A4 than Ritonavir
  作者：Irina F. Sevrioukova、Thomas L. Poulos

  DOI：10.1021/jm400288z

  日期：2013.5.9

  Utilization of the cytochrome P450 3A4 (CYP3A4) inhibitor ritonavir as a pharmacoenhancer for anti-HIV drugs revolutionized the treatment of HIV infection. However, owing to ritonavir-related complications, there is a need for development of new CYP3A4 inhibitors with improved pharmacochemical properties, which requires a full understanding of the CYP3A4 inactivation mechanisms and the unraveling of possible inhibitor binding modes. We investigated the mechanism of CYP3A4 interaction with three desoxyritonavir analogues, containing the heme-ligating imidazole, oxazole, or pyridine group instead of the thiazole moiety (compounds 1, 2, and 3, respectively). Our data show that compound 3 is superior to ritonavir in terms of binding affinity and inhibitory potency owing to greater flexibility and the ability to adopt a conformation that minimizes steric clashing and optimizes protein-ligand interactions. Additionally, Ser119 was identified as a key residue assisting binding of ritonavir-like inhibitors, which emphasizes the importance of polar interactions in the CYP3A4-ligand association.