ethyl 1-(3-hydroxypropyl)-2-(m-tolyl)pyrimidin-6(1H)-one-5-carboxylate | 340011-19-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: ethyl 1-(3-hydroxypropyl)-2-(m-tolyl)pyrimidin-6(1H)-one-5-carboxylate
• CAS: 340011-19-0
• 化学式: C₁₇H₂₀N₂O₄
• 分子量: 316.357
• InChiKey: GFSYFBRLYHZZRM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.78
• 重原子数：
  23.0
• 可旋转键数：
  6.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  81.42
• 氢给体数：
  1.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  ethyl 1-(3-hydroxypropyl)-2-(m-tolyl)pyrimidin-6(1H)-one-5-carboxylate 在 2,6-二甲基吡啶 、 二苯基膦叠氮化物 、 三乙胺 、 lithium iodide 作用下， 以 1,4-二氧六环 、 吡啶 、 二氯甲烷 为溶剂， 反应 29.0h， 生成 1-[5-benzyloxycarbonylamino-6-oxo-2-(m-tolyl)-1,6-dihydro-1-pyrimidinyl]-3-[(tert-butyldimethylsilyl)oxy]propane
  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：

  ethyl 3-methylbenzimidate hydrochloride 以 乙醇 为溶剂， 反应 19.0h， 生成 ethyl 1-(3-hydroxypropyl)-2-(m-tolyl)pyrimidin-6(1H)-one-5-carboxylate
  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