(S)-2-Amino-3-phenyl-propionic acid 2-(2-amino-6-oxo-1,6-dihydro-purin-9-ylmethoxy)-ethyl ester | 355117-38-3

• 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: (S)-2-Amino-3-phenyl-propionic acid 2-(2-amino-6-oxo-1,6-dihydro-purin-9-ylmethoxy)-ethyl ester
• 英文别名: 2-[(2-amino-6-oxo-1H-purin-9-yl)methoxy]ethyl (2S)-2-amino-3-phenylpropanoate
• CAS: 355117-38-3
• 化学式: C₁₇H₂₀N₆O₄
• 分子量: 372.384
• InChiKey: RXQQWJGSMMOFRU-LBPRGKRZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.3
• 重原子数：
  27
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  147
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (S)-2-Amino-3-phenyl-propionic acid 2-(2-amino-6-oxo-1,6-dihydro-purin-9-ylmethoxy)-ethyl ester 以 phosphate buffer 为溶剂， 生成 阿昔洛韦
  参考文献：
  名称：

  Chemical stability, enzymatic hydrolysis, and nasal uptake of amino acid ester prodrugs of acyclovir

  摘要：

  The objective of this work was to improve nasal absorption of relatively impermeable small drug molecules via an amino acid prodrug approach. Acyclovir was selected as a model drug. L-Aspartate beta -ester, L-lysyl, and L-phenylalanyl esters of acyclovir were synthesized to investigate their effectiveness in enhancing nasal absorption of acyclovir. A stability study was conducted in phosphate buffer under various pH conditions at 25 and 37 degreesC. Enzymatic hydrolysis in rat nasal washings and plasma was conducted at 37 degreesC. A rat in situ nasal perfusion technique was utilized in this investigation to examine the rate and extent of nasal absorption of amino acid prodrugs. The remaining analyte concentrations in the nasal perfusate were quantitated by reversed-phase high-performance liquid chromatography. The results revealed that the L-lysyl and L-phenylalanyl esters were less stable than L-aspartate beta -ester. The stability of all three esters decreased with increasing FH and temperature. L-phenylalanyl ester is highly susceptible to plasma esterases, with an in vitro half-life 1.33 min. The rat in situ nasal perfusion study revealed that the extent of nasal absorption of acyclovir, L-lysyl and L-phenylalanyl esters was not significant (p < 1%). L-Aspartate beta -ester was absorbed to the extent of similar to8% over 90 min of perfusion at an initial drug concentration of 100 muM. Nasal absorption of L-aspartate beta -ester of acyclovir was inhibited by L-asparagine but not by a dipeptide glycylsarcosine (Gly-Sar). The enhancement of acyclovir nasal absorption from the L-aspartate p-ester prodrug suggests that nasal uptake of this prodrug probably involves an active transport system. (C) 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:617-624, 2001.

  DOI：

  10.1002/1520-6017(200105)90:5<617::aid-jps1018>3.0.co;2-5
• 作为产物：
  描述：

  阿昔洛韦 在 palladium on activated charcoal 盐酸 、 4-二甲氨基吡啶 、 氢气 、 N,N'-二环己基碳二亚胺 作用下， 以 四氢呋喃 、 甲醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 76.0h， 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：

  Chemical stability, enzymatic hydrolysis, and nasal uptake of amino acid ester prodrugs of acyclovir

  摘要：

  The objective of this work was to improve nasal absorption of relatively impermeable small drug molecules via an amino acid prodrug approach. Acyclovir was selected as a model drug. L-Aspartate beta -ester, L-lysyl, and L-phenylalanyl esters of acyclovir were synthesized to investigate their effectiveness in enhancing nasal absorption of acyclovir. A stability study was conducted in phosphate buffer under various pH conditions at 25 and 37 degreesC. Enzymatic hydrolysis in rat nasal washings and plasma was conducted at 37 degreesC. A rat in situ nasal perfusion technique was utilized in this investigation to examine the rate and extent of nasal absorption of amino acid prodrugs. The remaining analyte concentrations in the nasal perfusate were quantitated by reversed-phase high-performance liquid chromatography. The results revealed that the L-lysyl and L-phenylalanyl esters were less stable than L-aspartate beta -ester. The stability of all three esters decreased with increasing FH and temperature. L-phenylalanyl ester is highly susceptible to plasma esterases, with an in vitro half-life 1.33 min. The rat in situ nasal perfusion study revealed that the extent of nasal absorption of acyclovir, L-lysyl and L-phenylalanyl esters was not significant (p < 1%). L-Aspartate beta -ester was absorbed to the extent of similar to8% over 90 min of perfusion at an initial drug concentration of 100 muM. Nasal absorption of L-aspartate beta -ester of acyclovir was inhibited by L-asparagine but not by a dipeptide glycylsarcosine (Gly-Sar). The enhancement of acyclovir nasal absorption from the L-aspartate p-ester prodrug suggests that nasal uptake of this prodrug probably involves an active transport system. (C) 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:617-624, 2001.

  DOI：

  10.1002/1520-6017(200105)90:5<617::aid-jps1018>3.0.co;2-5

文献信息

• Liquid Chromatographic Resolution of Amino Acid Esters of Acyclovir Including Racemic Valacyclovir on Crown Ether-Based Chiral Stationary Phases
  作者：Seong Ae Ahn、Myung Ho Hyun

  DOI：10.1002/chir.22424

  日期：2015.12

  Valacyclovir, a potential prodrug for the treatment of patients with herpes simplex and herpes zoster, and its analogs were resolved on two chiral stationary phases (CSPs) based on (3,3’‐diphenyl‐1,1’‐binaphthyl)‐20‐crown‐6 covalently bonded to silica gel. In order to find out an appropriate mobile phase condition, various mobile phases consisting of various organic modifiers in water containing various

  Valacyclovir是一种潜在的治疗单纯疱疹和带状疱疹患者的前药，其类似物在基于（3,3'-diphenyl-1,1'-binaphthyl）-20-的两个手性固定相（CSP）上拆分Crown-6与硅胶共价键合。为了找出合适的流动相条件，将含有多种酸性改性剂的水中各种有机改性剂组成的各种流动相应用于伐昔洛韦及其类似物的拆分。当使用含有0.05 M，0.10 M或0.15 M高氯酸的水溶液中的30％乙腈作为流动相时，伐拉昔洛韦及其类似物在两种CSP上的分离系数（α）在2.49〜6.35和分辨率（R S）在2.95〜12.21的范围内。在这两种CSP之间，发现在二氧化硅表面上含有保护正辛基基团的残留硅烷醇的CSP比含有残留硅烷醇基的CSP更好。手性27：268-273，2015。©2015 Wiley Periodicals，Inc.
• 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.
• Chemical stability, enzymatic hydrolysis, and nasal uptake of amino acid ester prodrugs of acyclovir
  作者：Chun Yang、Hongwu Gao、Ashim K. Mitra

  DOI：10.1002/1520-6017(200105)90:5<617::aid-jps1018>3.0.co;2-5

  日期：2001.5

  The objective of this work was to improve nasal absorption of relatively impermeable small drug molecules via an amino acid prodrug approach. Acyclovir was selected as a model drug. L-Aspartate beta -ester, L-lysyl, and L-phenylalanyl esters of acyclovir were synthesized to investigate their effectiveness in enhancing nasal absorption of acyclovir. A stability study was conducted in phosphate buffer under various pH conditions at 25 and 37 degreesC. Enzymatic hydrolysis in rat nasal washings and plasma was conducted at 37 degreesC. A rat in situ nasal perfusion technique was utilized in this investigation to examine the rate and extent of nasal absorption of amino acid prodrugs. The remaining analyte concentrations in the nasal perfusate were quantitated by reversed-phase high-performance liquid chromatography. The results revealed that the L-lysyl and L-phenylalanyl esters were less stable than L-aspartate beta -ester. The stability of all three esters decreased with increasing FH and temperature. L-phenylalanyl ester is highly susceptible to plasma esterases, with an in vitro half-life 1.33 min. The rat in situ nasal perfusion study revealed that the extent of nasal absorption of acyclovir, L-lysyl and L-phenylalanyl esters was not significant (p < 1%). L-Aspartate beta -ester was absorbed to the extent of similar to8% over 90 min of perfusion at an initial drug concentration of 100 muM. Nasal absorption of L-aspartate beta -ester of acyclovir was inhibited by L-asparagine but not by a dipeptide glycylsarcosine (Gly-Sar). The enhancement of acyclovir nasal absorption from the L-aspartate p-ester prodrug suggests that nasal uptake of this prodrug probably involves an active transport system. (C) 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:617-624, 2001.