Premium
Dipeptidyl Peptidase IV (DPPIV/CD26)‐Based Prodrugs of Hydroxy‐Containing Drugs
Author(s) -
DiezTorrubia Alberto,
Cabrera Silvia,
Lambeir AnneMarie,
Balzarini Jan,
Camarasa MaríaJosé,
Velázquez Sonsoles
Publication year - 2012
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201100504
Subject(s) - prodrug , chemistry , dipeptidyl peptidase , dipeptide , moiety , dipeptidyl peptidase 4 , stereochemistry , amide , peptide bond , combinatorial chemistry , enzyme , peptide , biochemistry , medicine , diabetes mellitus , type 2 diabetes , endocrinology
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.