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Title
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Dipeptidyl peptidase IV-activated prodrugs of anti-varicella zoster virus bicyclic nucleoside analogues containing different self-cleavage spacer systems
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Author
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Abstract
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| 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. |
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Language
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English
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Source (journal)
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ChemMedChem. - Place of publication unknown
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Publication
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Place of publication unknown
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2012
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ISSN
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1860-7179
[print]
1860-7187
[online]
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DOI
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10.1002/CMDC.201200295
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Volume/pages
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7
:9
(2012)
, p. 1612-1622
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ISI
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000308042000011
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Full text (Publisher's DOI)
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Full text (publisher's version - intranet only)
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