O-[(5S)-5-[(6-amino-9H-purin-9-yl)methyl]-2-oxido-1,4,2-dioxaphosphinan-2-yl]-N-(2-methylpropyl)-(L)-tyrosinamide hydrochloride | 1345667-15-3

• 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: O-[(5S)-5-[(6-amino-9H-purin-9-yl)methyl]-2-oxido-1,4,2-dioxaphosphinan-2-yl]-N-(2-methylpropyl)-(L)-tyrosinamide hydrochloride
• 英文别名: iso-butyl (2S)-2-amino-3-(4-{[(2R,5S)-5-[(6-amino-9H-purin-9-yl)methyl]-2-oxo-1,4,2λ5-dioxaphosphinan-2-yl]oxy}phenyl)-propanoate hydrochloride；(2S)-2-amino-3-[4-[[(2R,5S)-5-[(6-aminopurin-9-yl)methyl]-2-oxo-1,4,2lambda5-dioxaphosphinan-2-yl]oxy]phenyl]-N-(2-methylpropyl)propanamide;hydrochloride；(2S)-2-amino-3-[4-[[(2R,5S)-5-[(6-aminopurin-9-yl)methyl]-2-oxo-1,4,2λ5-dioxaphosphinan-2-yl]oxy]phenyl]-N-(2-methylpropyl)propanamide;hydrochloride
• CAS: 1345667-15-3
• 化学式: C₂₂H₃₀N₇O₅P*ClH
• 分子量: 539.959
• InChiKey: VQXWEPQZEMMWHA-FSPKQRQJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.12
• 重原子数：
  36
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  170
• 氢给体数：
  4
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  O-[(5S)-5-[(6-amino-9H-purin-9-yl)methyl]-2-oxido-1,4,2-dioxaphosphinan-2-yl]-N-α-(tert-butoxycarbonyl)-N-(2-methylpropyl)-(L)-tyrosinamide 在 三氟乙酸 、 盐酸 作用下， 以 二氯甲烷 、 甲醇 为溶剂， 生成 O-[(5S)-5-[(6-amino-9H-purin-9-yl)methyl]-2-oxido-1,4,2-dioxaphosphinan-2-yl]-N-(2-methylpropyl)-(L)-tyrosinamide hydrochloride 、 O-[(5S)-5-[(6-amino-9H-purin-9-yl)methyl]-2-oxido-1,4,2-dioxaphosphinan-2-yl]-N-(2-methylpropyl)-(L)-tyrosinamide hydrochloride
  参考文献：
  名称：

  Tyrosine-Based 1-(S)-[3-Hydroxy-2-(phosphonomethoxy)propyl]cytosine and -adenine ((S)-HPMPC and (S)-HPMPA) Prodrugs: Synthesis, Stability, Antiviral Activity, and in Vivo Transport Studies

  摘要：

  Eight novel single amino acid (6-11) and dipeptide (12, 13) tyrosine P-O esters of cyclic cidofovir ((S)-cHPMPC, 4) and its cyclic adenine analogue ((S)-cHPMPA, 3) were synthesized and evaluated as prodrugs. In vitro IC50 values for the prodrugs (<0.1-50 mu M) vs vaccinia, cowpox, human cytomegalovirus, and herpes simplex type 1 virus were compared to those for the parent drugs ((S)-HPMPC, 2; (S)HPMPA, 1; IC50 0.3-35 mu M); there was no cytoxicity with KB or HFF cells at <= 100 mu M. The prodrugs exhibited a wide range of half-lives in rat intestinal homogenate at pH 6.5 (<30-1732 min) with differences of 3-10x between phostonate diastereomers. The tyrosine allcylamide derivatives of 3 and 4 were the most stable. (L)-Tyr-NH-i-Bu cHPMPA (11) was converted in rat or mouse plasma solely to two active metabolites and had significantly enhanced oral bioavailability vs parent drug 1 in a mouse model (39% vs <5%).

  DOI：

  10.1021/jm2001426