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.
Instituto de Química Médica (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain.
Alberto
A
Diez-Torrubia
Silvia
S
Cabrera
Ingrid
I
De Meester
María-José
MJ
Camarasa
Jan
J
Balzarini
Sonsoles
S
Velázquez
D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000378:metabolism* / Q000493:pharmacokinetics; D001682:Biological Availability; D018938:Caco-2 Cells; D002417:Cattle; D002644:Chickenpox / Q000188:drug therapy; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D006562:Herpes Zoster / Q000188:drug therapy; D014645:Herpesvirus 3, Human / Q000187:drug effects*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009705:Nucleosides / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D011355:Prodrugs / Q000737:chemistry* / Q000378:metabolism* / Q000493:pharmacokinetics; D044967:Serum / Q000378:metabolism; D012995:Solubility
D000998:Antiviral Agents; D009705:Nucleosides; D011355:Prodrugs; D018819:Dipeptidyl Peptidase 4