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 functionalize model drugs from one key intermediate was generated and applied 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 compared to those of the parent drugs, were examined. None of the peptide-coupled compounds seemed to be transported by hPepT1, though one of the peptide-coupled compounds had affinity for hPepT1. Interestingly, in one case the parent drug was actively effluxed, while the corresponding peptide-coupled prodrug was not. The low aqueous solubility of the parent compounds was not increased after attachment to a dipeptide. This suggests that only compounds with a certain intrinsic aqueous solubility should be targeted to hPepT1 by attachment to a dipeptide. Important information about the design of peptide-coupled drugs targeted for hPepT1 is presented.
Friedrichsen
G M
GM
Department of Medicinal Chemistry, The Royal Danish School of Pharmacy, Universitetsparken 2, DK-2100, Copenhagen, Denmark.
Jakobsen
P
P
Taub
M
M
Begtrup
M
M
D001592:Benzyl Alcohols / Q000494:pharmacology; D001693:Biological Transport, Active; D018938:Caco-2 Cells / Q000187:drug effects; D015820:Cadherins; D002352:Carrier Proteins / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D015195:Drug Design; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000378:metabolism*; D005952:Glucose-6-Phosphatase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007583:Jejunum / Q000378:metabolism; D007700:Kinetics; D026901:Membrane Transport Proteins; D008956:Models, Chemical; D000074011:Peptide Transporter 1; D010539:Permeability / Q000187:drug effects; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D021281:Quantitative Structure-Activity Relationship; D027981:Symporters; D014407:Tumor Cells, Cultured / Q000187:drug effects
D001592:Benzyl Alcohols; C490584:CDH17 protein, human; D015820:Cadherins; D002352:Carrier Proteins; D004151:Dipeptides; D004791:Enzyme Inhibitors; D026901:Membrane Transport Proteins; D000074011:Peptide Transporter 1; D011355:Prodrugs; C082186:SLC15A1 protein, human; D027981:Symporters; C067802:intestinal peptide-proton cotransporter; C004276:glutamylalanine; C004194:glycylsarcosine; D005952:Glucose-6-Phosphatase