2-[2-(4-fluorophenyl)-5-methoxysuccinylamino-6-oxo-1,6-dihydro-1-pyrimidinyl]-N-(1-benzyl-3,3,3-trifluoro-2-oxopropyl)acetamide | 184710-32-5

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: 2-[2-(4-fluorophenyl)-5-methoxysuccinylamino-6-oxo-1,6-dihydro-1-pyrimidinyl]-N-(1-benzyl-3,3,3-trifluoro-2-oxopropyl)acetamide
• CAS: 184710-32-5
• 化学式: C₂₇H₂₄F₄N₄O₆
• 分子量: 576.504
• InChiKey: HSHICYQPVOCTOT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  41.0
• 可旋转键数：
  11.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  136.46
• 氢给体数：
  2.0
• 氢受体数：
  8.0

反应信息

• 作为反应物：
  描述：

  2-[2-(4-fluorophenyl)-5-methoxysuccinylamino-6-oxo-1,6-dihydro-1-pyrimidinyl]-N-(1-benzyl-3,3,3-trifluoro-2-oxopropyl)acetamide 在 sodium hydroxide 作用下， 以 四氢呋喃 为溶剂， 反应 2.0h， 以87%的产率得到N-[1-[(1-Benzyl-3,3,3-trifluoro-2-oxo-propylcarbamoyl)-methyl]-2-(4-fluoro-phenyl)-6-oxo-1,6-dihydro-pyrimidin-5-yl]-succinamic acid
  参考文献：
  名称：

  Non-Peptidic inhibitors of human chymase. Synthesis, structure–activity relationships, and pharmacokinetic profiles of a series of 5-amino-6-oxo-1,6-dihydropyrimidine-containing trifluoromethyl ketones

  摘要：

  Chymase possesses a wide variety of actions, including promotion of angiotensin II production and histamine release from mast cells. However, due to a lack of effective inhibitors featuring both high inhibitory activity and high metabolic stability, the pathophysiological role of chymase has not been fully elucidated. We designed non-peptidic inhibitors based on the predicted binding mode of the peptidic chymase inhibitor Val-Pro-Phe-CF3 and demonstrated that the Val-Pro unit is replaceable with a (5-amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl)acetyl moiety. Structure-activity relationship studies revealed that phenyl substitution at the 2-position of the pyrimidinone ring is indispensable for high activity. The most potent compound 1h (K-i = 0.0506 muM) is superior in potency to the parent peptidic inhibitor Val-Pro-Phe-CF3 and has good selectivity for chymase over other proteases. The related analogue 1e was orally absorbed and maintained high plasma levels for at least 2 h. These results suggest that the derivatives reported here could be developed as agents for treatment of chymase-induced disease. (C) 2001 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(00)00244-3
• 作为产物：
  描述：

  3-amino-1,1,1-trifluoro-4-phenyl-2-butanol 在 二氯乙酸 、 三氟甲磺酸 、 sodium carbonate 、 1-羟基苯并三唑 、 苯甲醚 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 作用下， 以 四氢呋喃 、 二氯甲烷 、 二甲基亚砜 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 3.0h， 生成 2-[2-(4-fluorophenyl)-5-methoxysuccinylamino-6-oxo-1,6-dihydro-1-pyrimidinyl]-N-(1-benzyl-3,3,3-trifluoro-2-oxopropyl)acetamide
  参考文献：
  名称：

  Non-Peptidic inhibitors of human chymase. Synthesis, structure–activity relationships, and pharmacokinetic profiles of a series of 5-amino-6-oxo-1,6-dihydropyrimidine-containing trifluoromethyl ketones

  摘要：

  Chymase possesses a wide variety of actions, including promotion of angiotensin II production and histamine release from mast cells. However, due to a lack of effective inhibitors featuring both high inhibitory activity and high metabolic stability, the pathophysiological role of chymase has not been fully elucidated. We designed non-peptidic inhibitors based on the predicted binding mode of the peptidic chymase inhibitor Val-Pro-Phe-CF3 and demonstrated that the Val-Pro unit is replaceable with a (5-amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl)acetyl moiety. Structure-activity relationship studies revealed that phenyl substitution at the 2-position of the pyrimidinone ring is indispensable for high activity. The most potent compound 1h (K-i = 0.0506 muM) is superior in potency to the parent peptidic inhibitor Val-Pro-Phe-CF3 and has good selectivity for chymase over other proteases. The related analogue 1e was orally absorbed and maintained high plasma levels for at least 2 h. These results suggest that the derivatives reported here could be developed as agents for treatment of chymase-induced disease. (C) 2001 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(00)00244-3