title: Synthesis, physicochemical properties and antiviral activities of ester prodrugs of ganciclovir.
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.affiliation: Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 5005 Rockhill Road, Kansas City, MO 64110-2499, USA.
authors.forename: Kunal
authors.initials: K
authors.lastname: Patel
authors.forename: Shrija
authors.initials: S
authors.lastname: Trivedi
authors.forename: Shuanghui
authors.initials: S
authors.lastname: Luo
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhu
authors.forename: Dhananjay
authors.initials: D
authors.lastname: Pal
authors.forename: Earl R
authors.initials: ER
authors.lastname: Kern
authors.forename: Ashim K
authors.initials: AK
authors.lastname: Mitra
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation; D003587:Cytomegalovirus / Q000187:drug effects; D004151:Dipeptides / Q000737:chemistry; D004355:Drug Stability; D004952:Esters / Q000737:chemistry; D005123:Eye / Q000378:metabolism; D015774:Ganciclovir / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D018259:Herpesvirus 1, Human / Q000187:drug effects; D018258:Herpesvirus 2, Human / Q000187:drug effects; D006801:Humans; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008297:Male; D008826:Microbial Sensitivity Tests; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology; D011817:Rabbits; D012995:Solubility
chemical_list: D000998:Antiviral Agents; D004151:Dipeptides; D004952:Esters; D011355:Prodrugs; D015774:Ganciclovir