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Synthesis, physicochemical properties and antiviral activities of ester prodrugs of ganciclovir.
Int J Pharm 2005; 305(1-2):75-89IJ

Abstract

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.

Authors+Show Affiliations

Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 5005 Rockhill Road, Kansas City, MO 64110-2499, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

16242278

Citation

Patel, Kunal, et al. "Synthesis, Physicochemical Properties and Antiviral Activities of Ester Prodrugs of Ganciclovir." International Journal of Pharmaceutics, vol. 305, no. 1-2, 2005, pp. 75-89.
Patel K, Trivedi S, Luo S, et al. Synthesis, physicochemical properties and antiviral activities of ester prodrugs of ganciclovir. Int J Pharm. 2005;305(1-2):75-89.
Patel, K., Trivedi, S., Luo, S., Zhu, X., Pal, D., Kern, E. R., & Mitra, A. K. (2005). Synthesis, physicochemical properties and antiviral activities of ester prodrugs of ganciclovir. International Journal of Pharmaceutics, 305(1-2), pp. 75-89.
Patel K, et al. Synthesis, Physicochemical Properties and Antiviral Activities of Ester Prodrugs of Ganciclovir. Int J Pharm. 2005 Nov 23;305(1-2):75-89. PubMed PMID: 16242278.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Synthesis, physicochemical properties and antiviral activities of ester prodrugs of ganciclovir. AU - Patel,Kunal, AU - Trivedi,Shrija, AU - Luo,Shuanghui, AU - Zhu,Xiaodong, AU - Pal,Dhananjay, AU - Kern,Earl R, AU - Mitra,Ashim K, Y1 - 2005/10/19/ PY - 2005/01/11/received PY - 2005/08/30/revised PY - 2005/08/31/accepted PY - 2005/10/26/pubmed PY - 2006/3/29/medline PY - 2005/10/26/entrez SP - 75 EP - 89 JF - International journal of pharmaceutics JO - Int J Pharm VL - 305 IS - 1-2 N2 - 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. SN - 0378-5173 UR - https://www.unboundmedicine.com/medline/citation/16242278/Synthesis_physicochemical_properties_and_antiviral_activities_of_ester_prodrugs_of_ganciclovir_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0378-5173(05)00603-4 DB - PRIME DP - Unbound Medicine ER -