benzyl N-[1-[2-[[2-[tert-butyl(dimethyl)silyl]oxy-1,1,1-trifluoro-4-methylpentan-3-yl]amino]-2-oxoethyl]-4-(2,2-dimethoxyethylcarbamoyl)-2-oxo-6-phenylpyridin-3-yl]carbamate | 1026592-89-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: benzyl N-[1-[2-[[2-[tert-butyl(dimethyl)silyl]oxy-1,1,1-trifluoro-4-methylpentan-3-yl]amino]-2-oxoethyl]-4-(2,2-dimethoxyethylcarbamoyl)-2-oxo-6-phenylpyridin-3-yl]carbamate
• CAS: 1026592-89-1
• 化学式: C₃₈H₅₁F₃N₄O₈Si
• 分子量: 776.926
• InChiKey: UXFBQLPERHQAIB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.71
• 重原子数：
  54
• 可旋转键数：
  18
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  145
• 氢给体数：
  3
• 氢受体数：
  11

反应信息

• 作为反应物：
  描述：

  benzyl N-[1-[2-[[2-[tert-butyl(dimethyl)silyl]oxy-1,1,1-trifluoro-4-methylpentan-3-yl]amino]-2-oxoethyl]-4-(2,2-dimethoxyethylcarbamoyl)-2-oxo-6-phenylpyridin-3-yl]carbamate 以 N,N-二甲基甲酰胺 为溶剂， 反应 2.5h， 生成 N-[2-[tert-butyl(dimethyl)silyl]oxy-1,1,1-trifluoro-4-methylpentan-3-yl]-2-[3-(2,2-dimethoxyethyl)-2,4,8-trioxo-6-phenyl-1H-pyrido[3,4-d]pyrimidin-7-yl]acetamide
  参考文献：
  名称：

  Nonpeptidic Inhibitors of Human Neutrophil Elastase. 7. Design, Synthesis, and in Vitro Activity of a Series of Pyridopyrimidine Trifluoromethyl Ketones

  摘要：

  Using molecular modeling and the information derived from X-ray crystal structures of human neutrophil elastase (HNE) and porcine pancreatic elastase (PPE) complexed to peptidic ligands, we have developed a new series of nonpeptidic inhibitors of HNE, the pyridopyrimidine trifluoromethyl ketones (TFMKs). These bicyclic inhibitors were designed to extend the concept of the related pyridone trifluoromethyl ketones by incorporating a rigidly positioned carbonyl group to participate in a hydrogen bonding interaction with the backbone NH groups of Gly-218 and Gly-219 of the enzyme. In addition, the pyrimidine ring serves as a scaffold to vector substituents toward the S-5-S-4 subsites of the enzyme's extended binding pocket. Furthermore, the heteroatoms of the pyrimidine ring generally increase the aqueous solubility of the pyridopyrimidines relative to pyridone TFMKs. Pyridopyrimidine TFMKs containing a 6-phenyl substituent afforded potent inhibitors of elastase, and several inhibitors from this class of compounds possessed aqueous solubilities of > 0.1 mg/mL and K-i values of less than or equal to 10 nM.

  DOI：

  10.1021/jm950684z
• 作为产物：
  描述：

  N,N-二甲基苯甲酰胺 在 lithium hydroxide 、 草酰氯 、 TEA 、 叠氮磷酸二苯酯 、 sodium hydride 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 lithium iodide 作用下， 以 1,4-二氧六环 、 吡啶 、 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 120.0 ℃ 、133.32 Pa 条件下， 反应 73.5h， 生成 benzyl N-[1-[2-[[2-[tert-butyl(dimethyl)silyl]oxy-1,1,1-trifluoro-4-methylpentan-3-yl]amino]-2-oxoethyl]-4-(2,2-dimethoxyethylcarbamoyl)-2-oxo-6-phenylpyridin-3-yl]carbamate
  参考文献：
  名称：

  Nonpeptidic Inhibitors of Human Neutrophil Elastase. 7. Design, Synthesis, and in Vitro Activity of a Series of Pyridopyrimidine Trifluoromethyl Ketones

  摘要：

  Using molecular modeling and the information derived from X-ray crystal structures of human neutrophil elastase (HNE) and porcine pancreatic elastase (PPE) complexed to peptidic ligands, we have developed a new series of nonpeptidic inhibitors of HNE, the pyridopyrimidine trifluoromethyl ketones (TFMKs). These bicyclic inhibitors were designed to extend the concept of the related pyridone trifluoromethyl ketones by incorporating a rigidly positioned carbonyl group to participate in a hydrogen bonding interaction with the backbone NH groups of Gly-218 and Gly-219 of the enzyme. In addition, the pyrimidine ring serves as a scaffold to vector substituents toward the S-5-S-4 subsites of the enzyme's extended binding pocket. Furthermore, the heteroatoms of the pyrimidine ring generally increase the aqueous solubility of the pyridopyrimidines relative to pyridone TFMKs. Pyridopyrimidine TFMKs containing a 6-phenyl substituent afforded potent inhibitors of elastase, and several inhibitors from this class of compounds possessed aqueous solubilities of > 0.1 mg/mL and K-i values of less than or equal to 10 nM.

  DOI：

  10.1021/jm950684z