[(S)-2-Phenyl-1-(pyridin-2-yldisulfanylmethyl)-ethyl]-carbamic acid tert-butyl ester | 141437-86-7

• 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: [(S)-2-Phenyl-1-(pyridin-2-yldisulfanylmethyl)-ethyl]-carbamic acid tert-butyl ester
• 英文别名: tert-butyl N-[(2S)-1-phenyl-3-(pyridin-2-yldisulfanyl)propan-2-yl]carbamate
• CAS: 141437-86-7
• 化学式: C₁₉H₂₄N₂O₂S₂
• 分子量: 376.544
• InChiKey: UUKZOQLPOSKRJG-INIZCTEOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.96
• 重原子数：
  25.0
• 可旋转键数：
  7.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  51.22
• 氢给体数：
  1.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  [(S)-2-Phenyl-1-(pyridin-2-yldisulfanylmethyl)-ethyl]-carbamic acid tert-butyl ester 在 三氟乙酸 作用下， 以 乙醇 、 二氯甲烷 为溶剂， 反应 3.0h， 生成 [2-((S)-2-Amino-3-phenyl-propyldisulfanylmethyl)-3-phenyl-propionylamino]-acetic acid benzyl ester
  参考文献：
  名称：

  Mixed-inhibitor-prodrug as a new approach toward systemically active inhibitors of enkephalin-degrading enzymes

  摘要：

  In order to evaluate the possible advantages of potentiating the effects of the endogenous enkephalins, to obtain analgesia without the serious drawbacks of morphine, it was essential to design systemically active compounds which inhibit the two metabolizing enzymes, aminopeptidase N (APN) and neutral endopeptidase 24.11 (NEP). A new concept combining the idea of "prodrug" and "mixed inhibitor" was therefore developed. Given the high efficiency of beta-mercaptoalkylamines as APN inhibitors and of N-(mercaptoacyl) amino acids as NEP inhibitors, compounds associating these molecules through disulfide or thioester bonds, which are known to increase lipophilicity and to favor passage across the blood-brain barrier, have been synthesized. An HPLC study indicated that the disulfide bridge was resistant to serum enzymes but was cleaved by brain membrane homogenates, suggesting that the active inhibitors were released in the central nervous system. The validity of the approach was verified by the efficient antinociceptive responses obtained in the hot plate test in mice after iv administration of disulfide-containing inhibitors (ED50s of from 4 to 26 mg/kg on the jump latency time). The analgesic potencies of the "mixed inhibitor-prodrug" RB 101 [H2NCH(CH2CH2SCH3)CH2SSCH2CH(CH2Ph)CONHCH(CH2Ph)COOCH2Ph] after iv administration were three times greater than those of a similar combined dose of its two constitutive moieties. The separation of the two diastereoisomers constituting RB 101 showed that the analgesia has a stereochemical dependence, the (S,S,S)-isomer being more active than the (S,R,S)-isomer. Furthermore, in the tail flick test in the rat, RB 101 gave 38% analgesia at a dose of 80 mg/kg. Due to its high efficiency and its longer pharmacological effect, RB 101 was selected for a complete study of its analgesic properties.

  DOI：

  10.1021/jm00091a016
• 作为产物：
  描述：

  (S)-2-<(tert-Butoxycarbonyl)amino>-3-phenylpropyl thioacetate 在 sodium hydroxide 、 溶剂黄146 作用下， 以 乙醇 为溶剂， 反应 3.0h， 生成 [(S)-2-Phenyl-1-(pyridin-2-yldisulfanylmethyl)-ethyl]-carbamic acid tert-butyl ester
  参考文献：
  名称：

  Mixed-inhibitor-prodrug as a new approach toward systemically active inhibitors of enkephalin-degrading enzymes

  摘要：

  In order to evaluate the possible advantages of potentiating the effects of the endogenous enkephalins, to obtain analgesia without the serious drawbacks of morphine, it was essential to design systemically active compounds which inhibit the two metabolizing enzymes, aminopeptidase N (APN) and neutral endopeptidase 24.11 (NEP). A new concept combining the idea of "prodrug" and "mixed inhibitor" was therefore developed. Given the high efficiency of beta-mercaptoalkylamines as APN inhibitors and of N-(mercaptoacyl) amino acids as NEP inhibitors, compounds associating these molecules through disulfide or thioester bonds, which are known to increase lipophilicity and to favor passage across the blood-brain barrier, have been synthesized. An HPLC study indicated that the disulfide bridge was resistant to serum enzymes but was cleaved by brain membrane homogenates, suggesting that the active inhibitors were released in the central nervous system. The validity of the approach was verified by the efficient antinociceptive responses obtained in the hot plate test in mice after iv administration of disulfide-containing inhibitors (ED50s of from 4 to 26 mg/kg on the jump latency time). The analgesic potencies of the "mixed inhibitor-prodrug" RB 101 [H2NCH(CH2CH2SCH3)CH2SSCH2CH(CH2Ph)CONHCH(CH2Ph)COOCH2Ph] after iv administration were three times greater than those of a similar combined dose of its two constitutive moieties. The separation of the two diastereoisomers constituting RB 101 showed that the analgesia has a stereochemical dependence, the (S,S,S)-isomer being more active than the (S,R,S)-isomer. Furthermore, in the tail flick test in the rat, RB 101 gave 38% analgesia at a dose of 80 mg/kg. Due to its high efficiency and its longer pharmacological effect, RB 101 was selected for a complete study of its analgesic properties.

  DOI：

  10.1021/jm00091a016