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Title
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Dipeptidyl peptidase IV (DPPIV/CD26)-based prodrugs of hydroxy-containing drugs
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Author
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Abstract
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| We previously described a novel prodrug approach in which a di- or tetrapeptide moiety is linked to a wide variety of amine-containing drugs through an amide bond, which is specifically cleaved by dipeptidyl peptidase IV (DPPIV/CD26) activity. Herein we report the application of this prodrug approach to a variety of hydroxy-containing drugs (primary, secondary, tertiary, or aromatic hydroxy groups). We designed and studied tripartite prodrugs containing a dipeptide moiety (cleavable by DPPIV/CD26) and a valine as a hetero-bifunctional connector to link the dipeptide to the hydroxy group of the drug through a metabolically labile ester bond. The hydroxy-containing prodrugs showed various susceptibilities to hydrolysis by DPPIV/CD26 and serum, depending on the nature of the compound. Prodrugs of compounds containing a primary hydroxy group (as in didanosine) or a hydroxy moiety on an aromatic entity (as in acetaminophen) were most efficiently converted. In contrast, a tertiary hydroxy group was much less susceptible to conversion into its parent drug by DPPIV/CD26 or serum. A number of the prodrugs showed remarkable increases in water solubility relative to their parent drugs. |
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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.201100504
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Volume/pages
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7
:4
(2012)
, p. 618-628
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ISI
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000302073100010
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Full text (Publisher's DOI)
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