[(R)-[(2-methylpropan-2-yl)oxycarbonylamino]-phenylmethyl]-[(2S)-3-oxo-3-[[(2S)-1-oxo-1-phenylmethoxypropan-2-yl]amino]-2-[(4-phenylphenyl)methyl]propyl]phosphinic acid | 247147-08-6

• 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: [(R)-[(2-methylpropan-2-yl)oxycarbonylamino]-phenylmethyl]-[(2S)-3-oxo-3-[[(2S)-1-oxo-1-phenylmethoxypropan-2-yl]amino]-2-[(4-phenylphenyl)methyl]propyl]phosphinic acid
• CAS: 247147-08-6
• 化学式: C₃₈H₄₃N₂O₇P
• 分子量: 670.742
• InChiKey: JGQBZOSPMXIBNW-NKPPDARJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.9
• 重原子数：
  48
• 可旋转键数：
  16
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  131
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  [(R)-[(2-methylpropan-2-yl)oxycarbonylamino]-phenylmethyl]-[(2S)-3-oxo-3-[[(2S)-1-oxo-1-phenylmethoxypropan-2-yl]amino]-2-[(4-phenylphenyl)methyl]propyl]phosphinic acid 在 甲酸 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 生成 (S)-2-((S)-3-{((R)-Amino-phenyl-methyl)-[2-(2,2-dimethyl-propionylsulfanyl)-ethoxy]-phosphinoyl}-2-biphenyl-4-ylmethyl-propionylamino)-propionic acid benzyl ester
  参考文献：
  名称：

  Long Lasting Antinociceptive Properties of Enkephalin Degrading Enzyme (NEP and APN) Inhibitor Prodrugs

  摘要：

  Prodrugs of phosphinic dual inhibitors of the enkephalin degrading enzymes, neutral endopeptidase (NEP) and aminopeptidase N (APN), corresponding to the formula H3N+CH(R-1)P(O)(OR)CH2CH(CH(2)Bip)CONHCH(CH3)COOCH2Ph, with R-1 = CH3 or Ph and R being a benzyl ester, a S-acyl-2-thioethyl derivative, or an acyloxyalkyl group, were synthesized to improve the poor central bioavailability of their precursors. As expected, these compounds (50 mg/kg, iv or ip) induced long lasting (similar to2 h) antinociceptive responses in the hot plate test in mice with a ceiling effect varying between 25 and 42% of analgesia. A very rapid hydrolysis of the carboxylate ester contrasting with a slow deprotection of the phosphinate group (t(1/2) similar to 1 h) was observed in serum while 80% of free drug was obtained after 1 h incubation with brain membranes. These results account for the long duration of action observed with these prodrugs.

  DOI：

  10.1021/jm0102248
• 作为产物：
  描述：

  二碳酸二叔丁酯 在 sodium hydroxide 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 0.5h， 生成 [(R)-[(2-methylpropan-2-yl)oxycarbonylamino]-phenylmethyl]-[(2S)-3-oxo-3-[[(2S)-1-oxo-1-phenylmethoxypropan-2-yl]amino]-2-[(4-phenylphenyl)methyl]propyl]phosphinic acid
  参考文献：
  名称：

  Long Lasting Antinociceptive Properties of Enkephalin Degrading Enzyme (NEP and APN) Inhibitor Prodrugs

  摘要：

  Prodrugs of phosphinic dual inhibitors of the enkephalin degrading enzymes, neutral endopeptidase (NEP) and aminopeptidase N (APN), corresponding to the formula H3N+CH(R-1)P(O)(OR)CH2CH(CH(2)Bip)CONHCH(CH3)COOCH2Ph, with R-1 = CH3 or Ph and R being a benzyl ester, a S-acyl-2-thioethyl derivative, or an acyloxyalkyl group, were synthesized to improve the poor central bioavailability of their precursors. As expected, these compounds (50 mg/kg, iv or ip) induced long lasting (similar to2 h) antinociceptive responses in the hot plate test in mice with a ceiling effect varying between 25 and 42% of analgesia. A very rapid hydrolysis of the carboxylate ester contrasting with a slow deprotection of the phosphinate group (t(1/2) similar to 1 h) was observed in serum while 80% of free drug was obtained after 1 h incubation with brain membranes. These results account for the long duration of action observed with these prodrugs.

  DOI：

  10.1021/jm0102248

文献信息

• Long Lasting Antinociceptive Properties of Enkephalin Degrading Enzyme (NEP and APN) Inhibitor Prodrugs
  作者：Huixiong Chen、Florence Noble、Bernard P. Roques、Marie-Claude Fournié-Zaluski

  DOI：10.1021/jm0102248

  日期：2001.10.1

  Prodrugs of phosphinic dual inhibitors of the enkephalin degrading enzymes, neutral endopeptidase (NEP) and aminopeptidase N (APN), corresponding to the formula H3N+CH(R-1)P(O)(OR)CH2CH(CH(2)Bip)CONHCH(CH3)COOCH2Ph, with R-1 = CH3 or Ph and R being a benzyl ester, a S-acyl-2-thioethyl derivative, or an acyloxyalkyl group, were synthesized to improve the poor central bioavailability of their precursors. As expected, these compounds (50 mg/kg, iv or ip) induced long lasting (similar to2 h) antinociceptive responses in the hot plate test in mice with a ceiling effect varying between 25 and 42% of analgesia. A very rapid hydrolysis of the carboxylate ester contrasting with a slow deprotection of the phosphinate group (t(1/2) similar to 1 h) was observed in serum while 80% of free drug was obtained after 1 h incubation with brain membranes. These results account for the long duration of action observed with these prodrugs.