Dipeptidyl Peptidase IV (DPPIV/CD26)-Based Prodrugs of Hydroxy-Containing Drugs

作者：Diez Torrubia Alberto^*; Cabrera Silvia; Lambeir Anne Marie; Balzarini Jan; Camarasa Maria Jose; Velazquez Sonsoles

来源：ChemMedChem, 2012, 7(4): 618-628.

DOI：10.1002/cmdc.201100504

• CD26
• dipeptidyl peptidase IV
• hydroxy-containing drugs
• peptides
• prodrugs

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.

• 出版日期2012-4
• 单位河北医科大学