[5-Benzyloxycarbonylamino-2-(3-methoxy-phenyl)-6-oxo-6H-pyrimidin-1-yl]-acetic acid

• 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: [5-Benzyloxycarbonylamino-2-(3-methoxy-phenyl)-6-oxo-6H-pyrimidin-1-yl]-acetic acid
• 英文别名: 2-[2-(3-Methoxyphenyl)-6-oxo-5-(phenylmethoxycarbonylamino)pyrimidin-1-yl]acetic acid；2-[2-(3-methoxyphenyl)-6-oxo-5-(phenylmethoxycarbonylamino)pyrimidin-1-yl]acetic acid
• 化学式: C₂₁H₁₉N₃O₆
• 分子量: 409.398
• InChiKey: SIONMMAAJJKSMI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  30
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  118
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  2-amino-1-hydroxy-1-[5-(methoxy-carbonyl)benzoxazol-2-yl]-3-phenylpropane 、 [5-Benzyloxycarbonylamino-2-(3-methoxy-phenyl)-6-oxo-6H-pyrimidin-1-yl]-acetic acid 在 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 N,N-二甲基甲酰胺 为溶剂， 反应 4.0h， 生成 2-(2-{2-[5-Benzyloxycarbonylamino-2-(3-methoxy-phenyl)-6-oxo-6H-pyrimidin-1-yl]-acetylamino}-1-hydroxy-3-phenyl-propyl)-benzooxazole-5-carboxylic acid methyl ester
  参考文献：
  名称：

  非肽α-酮杂环作为人类糜酶的新型抑制剂的合成，构效关系和药代动力学概况。

  摘要：

  我们基于肽化合物（1）的结构设计了非肽糜酶抑制剂，并证明了作为P3-P2支架的嘧啶酮骨架和作为P1羰基活化基团的杂环的组合可以用作非肽糜酶抑制剂。尤其是，引入异质双环化合物（如苯并恶唑）会产生更强的糜蛋白酶抑制活性。详细的结构活性关系研究对嘧啶酮环的2位上的苯并恶唑部分和取代基表明，2r（Y-40079）具有最强的糜蛋白酶抑制活性（K（i）= 4.85 nM）。该化合物对非人类来源的乳糜也有效，并且相对于其他蛋白酶显示出对乳糜的良好选择性。大鼠的药代动力学研究表明，口服后2r吸收缓慢，并显示令人满意的生物利用度（BA）（T（max）= 6.0 +/- 2.3 h，BA = 19.3 +/- 6.6％，t（1/2）= 35.7 +/- 13.3小时）。总之，2r是一种新型的，有效的，口服活性的糜酶抑制剂，它将是阐明糜酶的病理生理作用的有用工具。

  DOI：

  10.1021/jm000496v

文献信息

• Synthesis, Structure−Activity Relationships, and Pharmacokinetic Profiles of Nonpeptidic Difluoromethylene Ketones as Novel Inhibitors of Human Chymase
  作者：Fumihiko Akahoshi、Atsuyuki Ashimori、Hiroshi Sakashita、Takuya Yoshimura、Masahiro Eda、Teruaki Imada、Masahide Nakajima、Naoko Mitsutomi、Shigeki Kuwahara、Tatsuyuki Ohtsuka、Chikara Fukaya、Mizuo Miyazaki、Norifumi Nakamura

  DOI：10.1021/jm000497n

  日期：2001.4.1

  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.