Model prodrugs designed for the intestinal peptide transporter. A synthetic approach for coupling of hydroxy-containing compounds to dipeptides

The human peptide transporter, hPepT1. Situated in the small intestine, may be exploited to increase absorption of drugs or model drugs by attaching t hem 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 hydrol ysable ester linkages. Furthermore, a number of benzyl alcohols with variou s substituents in the 4-position of the phenyl ring were coupled to D-Asp-A la and D-Glu-Ala, Ideally. a prodrug should be stable in the upper small in testine and be converted to the parent drug during or after transport into the blood circulation. Therefore, we investigated the influence of the elec tronegativity of the substituent in the 4-position of the phenyl ring on st ability in aqueous solution at pH 6.0 and 7.4, corresponding to pH in jejun um and blood, respectively. In addition, the influence of the electronegati vity of the substituent on stability upon storage was examined. Model prodr ugs containing electron donating substituents in the 4-position of the phen yl ring decomposed upon storage, while model prodrugs containing no substit uents or electron withdrawing substituents in the 4-position were stable. I n aqueous solution (pH 6.0 and 7.4), electron withdrawing substituents in t he 4-position decreased the half-life of the model prodrug. These data prov ide important information on stability of this kind of model prodrugs upon storage and under aqueous conditions. The results may be applied in the rat ional design of oligopeptide ester prodrugs to obtain prodrugs, which are s table upon storage and have an optimal release profile of the drug. (C) 200 1 Elsevier Science BY, All rights reserved.