Synthesis, physicochemical properties and antiviral activities of ester prodrugs of ganciclovir.
Synthesis, physicochemical properties and antiviral activities of ester prodrugs of ganciclovir.
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DOI：
10.1016/j.ijpharm.2005.08.024
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发表时间：
2005-11
影响因子：
5.8
通讯作者：
K. Patel;Shrija Trivedi;Shuanghui Luo;Xiaodong Zhu;D. Pal;E. Kern;A. Mitra
中科院分区：
文献类型：
--
作者：
K. Patel;Shrija Trivedi;Shuanghui Luo;Xiaodong Zhu;D. Pal;E. Kern;A. Mitra
本研究的目的是合成更昔洛韦（GCV）的一系列双酯前药，以提高其眼用和口服生物利用度及治疗活性。测定了GCV前药的溶解度、logP、pH稳定性、体外抗病毒活性、细胞毒性、抑制特性和眼组织水解。发现Val-Val-GCV和Val-Gly-GCV二酯与Val-GCV和Gly-Val-GCV相比表现出更大的水稳定性，而眼组织水解证明Val-Gly-GCV和Gly-Val-GCV更稳定。Val-Val-GCV和Val-GCV二酯是最亲脂的化合物，并且预测其分配系数分别为GCV的295倍和12倍。所有前药均具有比母体药物GCV高得多的水溶性。兔眼中的离体摄取表明前药具有高摄取潜力。与GCV相比，前药显示细胞毒性没有增加，相反，它们对人巨细胞病毒（HCMV）以及HSV-1和HSV-2的效力显著增加。这应该允许在比目前使用的药物更容易实现的较低浓度下观察到治疗反应。总之，二酯GCV前药表现出优异的化学稳定性、高水溶性和显著增强的针对疱疹病毒的抗病毒效力，而细胞毒性没有任何增加。
The purpose of this study was to synthesize a series of diester prodrugs of ganciclovir (GCV), for improving ocular and oral bioavailability and therapeutic activity. Solubility, logP, pH stability profile, in vitro antiviral activity, cytotoxicity, inhibition profile and ocular tissue hydrolysis of the GCV prodrugs were measured. Val–Val–GCV and Val–Gly–GCV diesters were found to exhibit greater aqueous stability compared to Val–GCV and Gly–Val–GCV while ocular tissue hydrolysis demonstrated Val–Gly–GCV and Gly–Val–GCV to be more stable. Val–Val–GCV and Val–GCV diesters were the most lipophilic compounds and were predicted to possess a partition coefficient 295- and 12-fold greater than that of GCV, respectively. All the prodrugs possess much higher aqueous solubility than the parent drug GCV. Ex vivo uptake in the rabbit eye indicates that the prodrugs have high uptake potential. The prodrugs showed no increase in cytotoxicity compared to GCV, instead there was a marked increase in their potency against human cytomegalovirus (HCMV) as well as HSV-1 and HSV-2. This should allow therapeutic response to be seen at a lower concentration that can be achieved more easily, than the drugs currently being used. In conclusion, the diester GCV prodrugs demonstrated excellent chemical stability, high aqueous solubility and markedly enhanced antiviral potency against the herpes viruses without any increase in cytotoxicity.