Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Chemistry, Medicinal, Pharmacology & Pharmacy, CD26, dipeptidyl peptidase IV, peptides, prodrugs, self-cleavage spacers, PYRIMIDINE NUCLEOSIDES, PARTITION-COEFFICIENTS, REVERSE-TRANSCRIPTASE, SELECTIVE-INHIBITION, AQUEOUS SOLUBILITY, ANTIVIRAL ACTIVITY, CONTAINING DRUGS, PROSTATE-CANCER, DESIGN, POTENT, Animals, Antiviral Agents, Biological Availability, Caco-2 Cells, Cattle, Chickenpox, Dipeptidyl Peptidase 4, Herpes Zoster, Herpesvirus 3, Human, Humans, Mice, Mice, Inbred BALB C, Nucleosides, Prodrugs, Serum, Solubility, 0304 Medicinal and Biomolecular Chemistry, 0305 Organic Chemistry, 1115 Pharmacology and Pharmaceutical Sciences, Medicinal & Biomolecular Chemistry, 3404 Medicinal and biomolecular chemistry, 3405 Organic chemistry

Abstract:

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.