title: Model prodrugs designed for the intestinal peptide transporter. A synthetic approach for coupling of hydroxy-containing compounds to dipeptides.
abstract: The human peptide transporter, hPepT1, situated in the small intestine, may be exploited to increase absorption of drugs or model drugs by attaching them to a dipeptide, which is recognised by hPepT1. A synthetic protocol for this kind of model prodrugs was developed, in which model drugs containing a hydroxy group were attached to enzymatically stable dipeptides by hydrolysable ester linkages. Furthermore, a number of benzyl alcohols with various substituents in the 4-position of the phenyl ring were coupled to D-Asp-Ala and D-Glu-Ala. Ideally, a prodrug should be stable in the upper small intestine and be converted to the parent drug during or after transport into the blood circulation. Therefore, we investigated the influence of the electronegativity of the substituent in the 4-position of the phenyl ring on stability in aqueous solution at pH 6.0 and 7.4, corresponding to pH in jejunum and blood, respectively. In addition, the influence of the electronegativity of the substituent on stability upon storage was examined. Model prodrugs containing electron donating substituents in the 4-position of the phenyl ring decomposed upon storage, while model prodrugs containing no substituents or electron withdrawing substituents in the 4-position were stable. In aqueous solution (pH 6.0 and 7.4), electron withdrawing substituents in the 4-position decreased the half-life of the model prodrug. These data provide important information on stability of this kind of model prodrugs upon storage and under aqueous conditions. The results may be applied in the rational design of oligopeptide ester prodrugs to obtain prodrugs, which are stable upon storage and have an optimal release profile of the drug.
authors.affiliation: Department of Medicinal Chemistry, the Royal Danish School of Pharmacy, Universitetsparken 2, DK-2100, Copenhagen, Denmark.
authors.forename: G M
authors.initials: GM
authors.lastname: Friedrichsen
authors.forename: C U
authors.initials: CU
authors.lastname: Nielsen
authors.forename: B
authors.initials: B
authors.lastname: Steffansen
authors.forename: M
authors.initials: M
authors.lastname: Begtrup
mesh_terms: D001592:Benzyl Alcohols; D015820:Cadherins; D002264:Carboxylic Acids / Q000138:chemical synthesis; D002352:Carrier Proteins / Q000138:chemical synthesis*; D004151:Dipeptides / Q000737:chemistry*; D015195:Drug Design; D004355:Drug Stability; D006207:Half-Life; D006863:Hydrogen-Ion Concentration; D006900:Hydroxylation; D007583:Jejunum / Q000378:metabolism; D007700:Kinetics; D026901:Membrane Transport Proteins; D011355:Prodrugs / Q000138:chemical synthesis*
chemical_list: D001592:Benzyl Alcohols; C490584:CDH17 protein, human; D015820:Cadherins; D002264:Carboxylic Acids; D002352:Carrier Proteins; D004151:Dipeptides; D026901:Membrane Transport Proteins; D011355:Prodrugs; C067802:intestinal peptide-proton cotransporter