Application of enzymatically stable dipeptides for enhancement of intestinal permeability. Synthesis and in vitro evaluation of dipeptide-coupled compounds

Transport across the intestinal barrier of compounds with low permeability may be facilitated by targeting the human oligopeptide transporter, hPepT1. A flexible synthetic pathway for attaching compounds to dipeptides through ester or amide bonds was developed. Furthermore, a synthetic approach to f unctionalize model drugs from one key intermediate was generated and applie d to a glucose-6-phosphatase active model drug. The model drug was coupled to D-Glu-Ala through various linkers, and the G-6-Pase activity as well as the aqueous Solubility and transport properties of these prodrugs, as compa red to those of the parent drugs, were examined. None of the peptide-couple d compounds seemed to be transported by hPepT1, though one of the peptide-c oupled compounds had affinity for hPepT1. Interestingly, in one case the pa rent drug was actively effluxed, while the corresponding peptide-coupled pr odrug was not. The low aqueous solubility of the parent compounds was not i ncreased after attachment to a dipeptide. This suggests that only compounds with a certain intrinsic aqueous solubility should be targeted to hPepT1 b y attachment to a dipeptide. Important information about the design of pept ide-coupled drugs targeted for hPepT1 is presented. (C) 2001 Elsevier Scien ce Ltd. All rights reserved.