Prodrugs of HSV thymidine kinase inhibtors

Background: Because guanine-based HSV thymidine kinase inhibitors are not orally available, we synthesized various 6-deoxy prodrugs of these compounds and evaluated them with regard to solubility in water, oral bioavailability, and efficacy to prevent HSV-1 reactivation from latency in a mouse model. Methods: Organic synthesis was used to prepare compounds, HPLC to analyze hydrolytic conversion, MS to measure oral bioavailability, and mouse latent infection and induced reactivation to evaluate the efficacy of a specific prodrug. Results: Aqueous solubilities of prodrugs were improved, oxidation of prodrugs by animal cytosols occurred in vitro, and oral absorption of the optimal prodrug sacrovirTM (6-deoxy- mCF3PG) in the presence of the aqueous adjuvant Soluplus® and conversion to active compound N2-[3-(trifluoromethyl)pheny])guanine (mCF3PG) were accomplished in mice. Treatment of HSV-1 latent mice with sacrovirTM in 1 % Soluplus in drinking water significantly suppressed HSV-1 reactivation and viral genomic replication. Conclusions: Ad libitum oral delivery of sacrovirTM was effective in suppressing HSV-1 reactivation in ocularly-infected latent mice as measured by the numbers of mice shedding infectious virus at the ocular surface, numbers of trigeminal ganglia (TG) positive for infectious virus, number of corneas that had detectable infectious virus, and HSV-1 genome copy numbers in TG following reactivation. These results demonstrate the statistically significant effect of the prodrug on suppressing HSV-1 reactivation in vivo.