Dipeptidyl-peptidase IV (DPPIV/CD26)-based prodrugs of hydroxy-containing drugs

摘要

We previously described a novel prodrug approach in which a\uddi- or tetrapeptide moiety is linked to a wide variety of aminecontaining\uddrugs through an amide bond, which is specifically\udcleaved by dipeptidyl peptidase IV (DPPIV/CD26) activity.\udHerein we report the application of this prodrug approach to a\udvariety of hydroxy-containing drugs (primary, secondary, tertiary,\udor aromatic hydroxy groups). We designed and studied tripartite\udprodrugs containing a dipeptide moiety (cleavable by\udDPPIV/CD26) and a valine as a hetero-bifunctional connector\udto link the dipeptide to the hydroxy group of the drug\udthrough a metabolically labile ester bond. The hydroxy-containing\udprodrugs showed various susceptibilities to hydrolysis\udby DPPIV/CD26 and serum, depending on the nature of the\udcompound. Prodrugs of compounds containing a primary hydroxy\udgroup (as in didanosine) or a hydroxy moiety on an aromatic\udentity (as in acetaminophen) were most efficiently converted.\udIn contrast, a tertiary hydroxy group was much less susceptible\udto conversion into its parent drug by DPPIV/CD26 or\udserum. A number of the prodrugs showed remarkable increases\udin water solubility relative to their parent drugs.