title: Dipeptidyl peptidase IV dependent water-soluble prodrugs of highly lipophilic bicyclic nucleoside analogues.
abstract: We present the first report of the application of the dipeptidyl peptidase IV (DPPIV/CD26) based prodrug approach to hydroxy-containing drug derivatives. In particular, we applied this strategy to the highly lipophilic antiviral drug family of bicyclic furanopyrimidine nucleoside analogues (BCNA) in order to improve their physicochemical and pharmacokinetic properties. Our stability data demonstrated that the prodrugs efficiently release the parent BCNA drug upon selective conversion by purified DPPIV/CD26 and by soluble DPPIV/CD26 present in bovine, murine, and human serum. Vildagliptin, a specific inhibitor of DPPIV/CD26, was able to completely block the hydrolysis of the prodrugs in the presence of purified DPPIV/CD26 human, murine, and bovine serum. Several novel prodrugs showed remarkable increases in water solubility (up to more than 3 orders of magnitude) compared to the poorly soluble parent drug. We also demonstrated a markedly enhanced oral bioavailability of the prodrugs versus the parent drug in mice.
authors.affiliation: Instituto de Química Médica (CSIC), Juan de Cierva 3, E-28006 Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Diez-Torrubia
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Graciela
authors.initials: G
authors.lastname: Andrei
authors.forename: Robert
authors.initials: R
authors.lastname: Snoeck
authors.forename: Ingrid
authors.initials: I
authors.lastname: De Meester
authors.forename: María-José
authors.initials: MJ
authors.lastname: Camarasa
authors.forename: Sonsoles
authors.initials: S
authors.lastname: Velázquez
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D018938:Caco-2 Cells; D002417:Cattle; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D004355:Drug Stability; D005260:Female; D005663:Furans / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D014645:Herpesvirus 3, Human / Q000187:drug effects; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D006868:Hydrolysis; D051379:Mice; D009570:Nitriles / Q000494:pharmacology; D009705:Nucleosides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D012995:Solubility; D013329:Structure-Activity Relationship; D000077597:Vildagliptin; D014867:Water
chemical_list: D000998:Antiviral Agents; D054873:Dipeptidyl-Peptidase IV Inhibitors; D005663:Furans; D006574:Heterocyclic Compounds, 2-Ring; D009570:Nitriles; D009705:Nucleosides; D009842:Oligopeptides; D011355:Prodrugs; D011743:Pyrimidines; D011759:Pyrrolidines; D014867:Water; D000077597:Vildagliptin; D000218:Adamantane