benzyl 2-[2,4,8-trioxo-7-[2-oxo-2-[(1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl)amino]ethyl]-6-phenyl-1H-pyrido[3,4-d]pyrimidin-3-yl]acetate | 1027660-03-2

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: benzyl 2-[2,4,8-trioxo-7-[2-oxo-2-[(1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl)amino]ethyl]-6-phenyl-1H-pyrido[3,4-d]pyrimidin-3-yl]acetate
• CAS: 1027660-03-2
• 化学式: C₃₀H₂₉F₃N₄O₇
• 分子量: 614.578
• InChiKey: IGERAMGCVGNSSP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  44
• 可旋转键数：
  11
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  145
• 氢给体数：
  3
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  benzyl 2-[2,4,8-trioxo-7-[2-oxo-2-[(1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl)amino]ethyl]-6-phenyl-1H-pyrido[3,4-d]pyrimidin-3-yl]acetate 在 二氯乙酸 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 二甲基亚砜 、 甲苯 为溶剂， 反应 16.0h， 生成 {(R)-2,4,8-Trioxo-6-phenyl-7-[(3,3,3-trifluoro-1-isopropyl-2-oxo-propylcarbamoyl)-methyl]-1,4,7,8-tetrahydro-2H-pyrido[3,4-d]pyrimidin-3-yl}-acetic 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
• 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 、 四丁基氟化铵 、 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 四氢呋喃 、 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 78.0h， 生成 benzyl 2-[2,4,8-trioxo-7-[2-oxo-2-[(1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-yl)amino]ethyl]-6-phenyl-1H-pyrido[3,4-d]pyrimidin-3-yl]acetate
  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.