2-[(2-amino-6-oxo-1H-purin-9-yl)methoxy]ethyl (2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoate | 1160857-09-9

• 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: 2-[(2-amino-6-oxo-1H-purin-9-yl)methoxy]ethyl (2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoate
• CAS: 1160857-09-9
• 化学式: C₂₂H₂₈N₆O₆
• 分子量: 472.501
• InChiKey: UYXKICVDLQYWCE-HNNXBMFYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  34
• 可旋转键数：
  12
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  159
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  2-[(2-amino-6-oxo-1H-purin-9-yl)methoxy]ethyl (2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoate 在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 生成 (S)-2-Amino-3-phenyl-propionic acid 2-(2-amino-6-oxo-1,6-dihydro-purin-9-ylmethoxy)-ethyl ester
  参考文献：
  名称：

  Topical iontophoretic delivery of ionizable, biolabile aciclovir prodrugs: A rational approach to improve cutaneous bioavailability

  摘要：

  The objective was to investigate the topical iontophoretic delivery of a series of amino acid ester prodrugs of aciclovir (ACV-X, where ACV = aciclovir and X = Arg, Gly, Ile, Phe, Trp and Val) as a means to enhance cutaneous delivery of ACV. The newly synthesized prodrugs were characterized by H-1 NMR and high resolution mass spectrometry. Analytical methods using HPLC-UV were developed for their quantification and each method was validated. Investigation of solution stability as a function of pH showed that all ACV-X prodrugs were relatively stable in acid conditions at pH 2.0 and pH 5.5 for up to 8 h but susceptible to extensive hydrolysis at pH 7.4 and under alkaline conditions (pH 10). No ACV-X hydrolysis was observed after contact for 2 h with the external surface of porcine stratum corneum. However, there was significant hydrolysis following contact with the dermal surface of dermatomed porcine skin, in particular, for ACV-Arg. Passive transport of ACV and ACV-X prodrugs from aqueous solution after 2 h was below the limit of detection. Iontophoresis of ACV at 0.5 mA/cm(2) for 2 h led to modest ACV skin deposition (Q(DEP,ACV)) of 4.6 +/- 0.3 nmol/cm(2). In contrast, iontophoresis of ACV-X prodrugs under the same conditions produced order of magnitude increases in cutaneous deposition of ACV species, that is, Q(DEP,TOTAL) = Q(DEP,ACV) + Q(DEP,ACV-X). Q(DEP,TOTAL) for ACV-Gly, ACV-Val, ACV-Ile, ACV-Phe, ACV-Trp and ACV-Arg was 412.8 +/- 44.0, 358.8 +/- 66.8, 434.1 +/- 68.2, 249.8 +/- 81.4, 156.1 +/- 76.3, 785.9 +/- 78.1 nmol/cm(2), respectively. The extent of bioconversion of ACV -X to ACV in the skin was high and the proportion of ACV present ranged from 81% to 100%. The skin retention ratio, a measure of the selectivity of ACV species for deposition over permeation after iontophoretic delivery of ACV -X prodrugs, was dependent on both the rate of transport and the susceptibility to hydrolysis of the prodrugs. Skin deposition of ACV and its six prodrugs were investigated further as a function of current density (0.125, 0.25 and 0.5 mA/cm(2)); the effect of duration of current application (5,10, 30, 60 and 120 min) was evaluated using ACV-Arg and ACV-Ile. Iontophoresis of ACV-Arg and ACV-Ile at 0.25 mA/cm(2) for only 5 min resulted in the deposition of appreciable amounts of ACV (36.4 +/- 5.7 nmol/cm(2) and 40.3 +/- 6.1 nmol/cm(2), respectively), corresponding to supra-therapeutic average concentrations in skin against HSV-1 or HSV-2. The results demonstrated that cutaneous bioavailability of ACV could be significantly improved after short duration iontophoresis of ionizable, biolabile ACV -X prodrugs. (C) 2015 Elsevier B.V. All rights reserved.

  DOI：

  10.1016/j.ejpb.2015.12.002
• 作为产物：
  描述：

  阿昔洛韦 、 BOC-L-苯丙氨酸 在 4-二甲氨基吡啶 、 N,N'-二环己基碳二亚胺 作用下， 以 吡啶 、 二氯甲烷 为溶剂， 反应 50.0h， 生成 2-[(2-amino-6-oxo-1H-purin-9-yl)methoxy]ethyl (2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoate
  参考文献：
  名称：

  阿昔洛韦二肽前药的构效关系：对前药设计的启示

  摘要：

  评估了一系列抗病毒阿昔洛韦（ACV）的水溶性二肽酯前药的化学稳定性，细胞毒性以及对几种单纯疱疹-1型和-2型，牛痘，水疱性口腔炎，巨细胞病毒和水痘带状疱疹病毒的抗病毒活性。ACV二肽酯对疱疹病毒非常有活性，而与它们释放母体药物的速率无关。它们的最低细胞毒性浓度超过100μM，且产生的MCC / EC 50值低于ACV。当比较pH 7.4缓冲液中Phe-Gly酯和酰胺（ACV，齐多夫定，对乙酰氨基酚，卡托普利和伯氨喹）的反应性时，发现药物释放速率随药物离去基团能力的增加而增加。母体药物在人血浆中从Phe-Gly释放的速度明显比在pH 7.4缓冲液中释放快，因此表明基于二肽的前药方法可以成功地应用于含有硫醇，苯酚和胺官能团的生物活性剂。

  DOI：

  10.1016/j.ejmech.2008.08.009

文献信息

• Topical iontophoretic delivery of ionizable, biolabile aciclovir prodrugs: A rational approach to improve cutaneous bioavailability
  作者：Yong Chen、Ingo Alberti、Yogeshvar N. Kalia

  DOI：10.1016/j.ejpb.2015.12.002

  日期：2016.2

  The objective was to investigate the topical iontophoretic delivery of a series of amino acid ester prodrugs of aciclovir (ACV-X, where ACV = aciclovir and X = Arg, Gly, Ile, Phe, Trp and Val) as a means to enhance cutaneous delivery of ACV. The newly synthesized prodrugs were characterized by H-1 NMR and high resolution mass spectrometry. Analytical methods using HPLC-UV were developed for their quantification and each method was validated. Investigation of solution stability as a function of pH showed that all ACV-X prodrugs were relatively stable in acid conditions at pH 2.0 and pH 5.5 for up to 8 h but susceptible to extensive hydrolysis at pH 7.4 and under alkaline conditions (pH 10). No ACV-X hydrolysis was observed after contact for 2 h with the external surface of porcine stratum corneum. However, there was significant hydrolysis following contact with the dermal surface of dermatomed porcine skin, in particular, for ACV-Arg. Passive transport of ACV and ACV-X prodrugs from aqueous solution after 2 h was below the limit of detection. Iontophoresis of ACV at 0.5 mA/cm(2) for 2 h led to modest ACV skin deposition (Q(DEP,ACV)) of 4.6 +/- 0.3 nmol/cm(2). In contrast, iontophoresis of ACV-X prodrugs under the same conditions produced order of magnitude increases in cutaneous deposition of ACV species, that is, Q(DEP,TOTAL) = Q(DEP,ACV) + Q(DEP,ACV-X). Q(DEP,TOTAL) for ACV-Gly, ACV-Val, ACV-Ile, ACV-Phe, ACV-Trp and ACV-Arg was 412.8 +/- 44.0, 358.8 +/- 66.8, 434.1 +/- 68.2, 249.8 +/- 81.4, 156.1 +/- 76.3, 785.9 +/- 78.1 nmol/cm(2), respectively. The extent of bioconversion of ACV -X to ACV in the skin was high and the proportion of ACV present ranged from 81% to 100%. The skin retention ratio, a measure of the selectivity of ACV species for deposition over permeation after iontophoretic delivery of ACV -X prodrugs, was dependent on both the rate of transport and the susceptibility to hydrolysis of the prodrugs. Skin deposition of ACV and its six prodrugs were investigated further as a function of current density (0.125, 0.25 and 0.5 mA/cm(2)); the effect of duration of current application (5,10, 30, 60 and 120 min) was evaluated using ACV-Arg and ACV-Ile. Iontophoresis of ACV-Arg and ACV-Ile at 0.25 mA/cm(2) for only 5 min resulted in the deposition of appreciable amounts of ACV (36.4 +/- 5.7 nmol/cm(2) and 40.3 +/- 6.1 nmol/cm(2), respectively), corresponding to supra-therapeutic average concentrations in skin against HSV-1 or HSV-2. The results demonstrated that cutaneous bioavailability of ACV could be significantly improved after short duration iontophoresis of ionizable, biolabile ACV -X prodrugs. (C) 2015 Elsevier B.V. All rights reserved.
• Structure–activity relationships for dipeptide prodrugs of acyclovir: Implications for prodrug design
  作者：Cledir R. Santos、Rita Capela、Cláudia S.G.P. Pereira、Emília Valente、Luís Gouveia、Christophe Pannecouque、Erik De Clercq、Rui Moreira、Paula Gomes

  DOI：10.1016/j.ejmech.2008.08.009

  日期：2009.6

  A series of water-soluble dipeptide ester prodrugs of the antiviral acyclovir (ACV) were evaluated for their chemical stability, cytotoxicity, and antiviral activity against several strains of Herpes Simplex-1 and -2, vaccinia, vesicular stomatitis, cytomegalovirus and varicella zoster viruses. ACV dipeptide esters were very active against herpetic viruses, independently of the rate at which they liberate

  评估了一系列抗病毒阿昔洛韦（ACV）的水溶性二肽酯前药的化学稳定性，细胞毒性以及对几种单纯疱疹-1型和-2型，牛痘，水疱性口腔炎，巨细胞病毒和水痘带状疱疹病毒的抗病毒活性。ACV二肽酯对疱疹病毒非常有活性，而与它们释放母体药物的速率无关。它们的最低细胞毒性浓度超过100μM，且产生的MCC / EC 50值低于ACV。当比较pH 7.4缓冲液中Phe-Gly酯和酰胺（ACV，齐多夫定，对乙酰氨基酚，卡托普利和伯氨喹）的反应性时，发现药物释放速率随药物离去基团能力的增加而增加。母体药物在人血浆中从Phe-Gly释放的速度明显比在pH 7.4缓冲液中释放快，因此表明基于二肽的前药方法可以成功地应用于含有硫醇，苯酚和胺官能团的生物活性剂。