Dipeptidyl peptidase IV-activated prodrugs of anti-varicella zoster virus bicyclic nucleoside analogues containing different self-cleavage spacer systems.

A new type of double prodrug of the antiviral family of bicyclic nucleoside analogues (BCNA) bearing cyclization self-cleavage spacers between the Val-Pro dipeptide sequence as well as the parent compound were synthesized and evaluated with regard to activation by the DPPIV/CD26 enzyme and for their stability in human and bovine serum. In buffer solution, carbamate and ester prodrugs were found to be chemically stable. Most prodrugs containing a dipeptidyl linker efficiently converted into the BCNA parent drug. In contrast, the Val-Pro alkyldiamino prodrugs converted predominantly into their alkyldiamino prodrug intermediates in the presence of CD26 and human serum. A marked increase in water solubility was observed for all prodrugs. In contrast to the parent compound, a tetrapeptide prodrug containing the Val-Val dipeptide as a self-cleavage spacer released substantial amounts of the BCNA parent drug at the basolateral side of Caco-2 cell cultures and exhibited 15- to 20-fold increased bioavailability in mice relative to the poorly bioavailable parent compound.