(4-Benzylcarbamoyl-1-{[2-(tert-butyl-dimethyl-silanyloxy)-3,3,3-trifluoro-1-isopropyl-propylcarbamoyl]-methyl}-2-oxo-1,2-dihydro-pyridin-3-yl)-carbamic acid benzyl ester | 1026415-73-5

• 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: (4-Benzylcarbamoyl-1-{[2-(tert-butyl-dimethyl-silanyloxy)-3,3,3-trifluoro-1-isopropyl-propylcarbamoyl]-methyl}-2-oxo-1,2-dihydro-pyridin-3-yl)-carbamic acid benzyl ester
• 英文别名: benzyl N-[4-(benzylcarbamoyl)-1-[2-[[2-[tert-butyl(dimethyl)silyl]oxy-1,1,1-trifluoro-4-methylpentan-3-yl]amino]-2-oxoethyl]-2-oxopyridin-3-yl]carbamate
• CAS: 1026415-73-5
• 化学式: C₃₅H₄₅F₃N₄O₆Si
• 分子量: 702.846
• InChiKey: KEYVMKJJAJDMEG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.62
• 重原子数：
  49
• 可旋转键数：
  15
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  126
• 氢给体数：
  3
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  (4-Benzylcarbamoyl-1-{[2-(tert-butyl-dimethyl-silanyloxy)-3,3,3-trifluoro-1-isopropyl-propylcarbamoyl]-methyl}-2-oxo-1,2-dihydro-pyridin-3-yl)-carbamic acid benzyl ester 在 二氯乙酸 、 四丁基氟化铵 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 四氢呋喃 、 二甲基亚砜 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 20.5h， 生成 2-(3-Benzyl-2,4,8-trioxo-1,2,3,4,7,8-hexahydropyrido[3,4-d]pyrimidin-7-yl)-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)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：

  dimethyl <2-(ethoxycarbonyl)ethylidene>malonate 在 lithium hydroxide 、 TEA 、 叠氮磷酸二苯酯 、 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 、 N,N-二甲基甲酰胺 为溶剂， 反应 60.0h， 生成 (4-Benzylcarbamoyl-1-{[2-(tert-butyl-dimethyl-silanyloxy)-3,3,3-trifluoro-1-isopropyl-propylcarbamoyl]-methyl}-2-oxo-1,2-dihydro-pyridin-3-yl)-carbamic acid benzyl ester
  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

文献信息

• Nonpeptidic Inhibitors of Human Neutrophil Elastase. 7. Design, Synthesis, and <i>in Vitro</i> Activity of a Series of Pyridopyrimidine Trifluoromethyl Ketones
  作者：Philip D. Edwards、Donald W. Andisik、Anne M. Strimpler、Bruce Gomes、Paul A. Tuthill

  DOI：10.1021/jm950684z

  日期：1996.1.1

  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.