2-[5-benzyloxycarbonylamino-6-oxo-2-(m-tolyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-benzyl-3,3-difluoro-2-hydroxy-3-(N-methylcarbamoyl)propyl]acetamide | 339169-57-2

• 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: 2-[5-benzyloxycarbonylamino-6-oxo-2-(m-tolyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-benzyl-3,3-difluoro-2-hydroxy-3-(N-methylcarbamoyl)propyl]acetamide
• 英文别名: benzyl N-[1-[2-[[4,4-difluoro-3-hydroxy-5-(methylamino)-5-oxo-1-phenylpentan-2-yl]amino]-2-oxoethyl]-2-(3-methylphenyl)-6-oxopyrimidin-5-yl]carbamate
• CAS: 339169-57-2
• 化学式: C₃₃H₃₃F₂N₅O₆
• 分子量: 633.652
• InChiKey: TZKAPXZOGZVZOY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  46
• 可旋转键数：
  13
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  149
• 氢给体数：
  4
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  2-[5-benzyloxycarbonylamino-6-oxo-2-(m-tolyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-benzyl-3,3-difluoro-2-hydroxy-3-(N-methylcarbamoyl)propyl]acetamide 在 10percent Pd/C 氢气 、 戴斯-马丁氧化剂 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 30.0h， 生成 4-[2-(5-Amino-6-oxo-2-m-tolyl-6H-pyrimidin-1-yl)-acetylamino]-2,2-difluoro-3-oxo-5-phenyl-pentanoic acid methylamide
  参考文献：
  名称：

  Synthesis, Structure−Activity Relationships, and Pharmacokinetic Profiles of Nonpeptidic Difluoromethylene Ketones as Novel Inhibitors of Human Chymase

  摘要：

  Potent human chymase inhibitors with high enzymatic selectivity and satisfactory metabolic stability were obtained by replacing the Val-Pro (P-3-P-2) dipeptide portion of the previously described inhibitor 1 with a nonpeptidic pyrimidinone skeleton. The potency of the novel compounds was further enhanced by the introduction of carbamoyl-substituted difluoromethylene ketone moieties. The most potent chymase inhibitor of the newly created series was 2u (Y-40018), which had a K-i of 2.62 nM. Compound 2u possessed high selectivity for human chymase since it lacked significant activity toward other representative human proteolytic enzymes. Moreover its strict specificity for human chymase suggested that 2u strongly inhibited human and canine chymases but not rat and mouse ones. Pharmacokinetic studies in rats and dogs indicated that 2u was absorbed rapidly after oral administration and had satisfactory bioavailability in these experimental animal species (rat, 17%; dog, 32%). In conclusion, 2u is a novel, potent, and orally active chymase inhibitor which would prove very useful in revealing the precise roles of the latter in various pathophysiological processes.

  DOI：

  10.1021/jm000497n
• 作为产物：
  描述：

  4-benzyl-4-benzyloxycarbonylamino-2,2-difluoro-3-hydroxybutanoic acid 在 10percent Pd/C N-乙基吗啉 、 盐酸 、 氢气 、 1-羟基苯并三唑一水物 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 49.0h， 生成 2-[5-benzyloxycarbonylamino-6-oxo-2-(m-tolyl)-1,6-dihydro-1-pyrimidinyl]-N-[1-benzyl-3,3-difluoro-2-hydroxy-3-(N-methylcarbamoyl)propyl]acetamide
  参考文献：
  名称：

  Synthesis, Structure−Activity Relationships, and Pharmacokinetic Profiles of Nonpeptidic Difluoromethylene Ketones as Novel Inhibitors of Human Chymase

  摘要：

  Potent human chymase inhibitors with high enzymatic selectivity and satisfactory metabolic stability were obtained by replacing the Val-Pro (P-3-P-2) dipeptide portion of the previously described inhibitor 1 with a nonpeptidic pyrimidinone skeleton. The potency of the novel compounds was further enhanced by the introduction of carbamoyl-substituted difluoromethylene ketone moieties. The most potent chymase inhibitor of the newly created series was 2u (Y-40018), which had a K-i of 2.62 nM. Compound 2u possessed high selectivity for human chymase since it lacked significant activity toward other representative human proteolytic enzymes. Moreover its strict specificity for human chymase suggested that 2u strongly inhibited human and canine chymases but not rat and mouse ones. Pharmacokinetic studies in rats and dogs indicated that 2u was absorbed rapidly after oral administration and had satisfactory bioavailability in these experimental animal species (rat, 17%; dog, 32%). In conclusion, 2u is a novel, potent, and orally active chymase inhibitor which would prove very useful in revealing the precise roles of the latter in various pathophysiological processes.

  DOI：

  10.1021/jm000497n