Dipeptidomimetic ketomethylene isosteres as pro-moieties for drug transport via the human intestinal di-/tripeptide transporter hPEPT1: design, synthesis, stability, and biological investigations.
Five dipeptidomimetic-based model prodrugs containing ketomethylene amide bond replacements were synthesized from readily available alpha,beta-unsaturated gamma-ketoesters. The model drug (BnOH) was attached to the C-terminus or to one of the side chain positions of the dipeptidomimetic. The stability, the affinity for the di-/tripeptide transporter hPEPT1, and the transepithelial transport properties of the model prodrugs were investigated. ValPsi[COCH(2)]Asp(OBn) was the compound with highest chemical stability in buffers at pH 6.0 and 7.4, with half-lives of 190 and 43 h, respectively. All five compounds showed high affinity for hPEPT1 (K(i) values < 1 mM), and PhePsi[COCH(2)]Asp(OBn) and ValPsi[COCH(2)]Asp(OBn) had the highest affinities with K(i) values of 68 and 19 microM, respectively. An hPEPT1-mediated transport component was demonstrated for the transepithelial transport of three compounds, a finding that was corroborated by hPEPT1-mediated intracellular uptake. The results indicate that the stabilized Phe-Asp and Val-Asp derivatives are promising pro-moieties in a prodrug approach targeting hPEPT1.
Våbenø
Jon
J
Department of Medicinal Chemistry, Institute of Pharmacy, University of Tromsø, N-9037 Tromsø, Norway.
Nielsen
Carsten Uhd
CU
Ingebrigtsen
Truls
T
Lejon
Tore
T
Steffansen
Bente
B
Luthman
Kristina
K
D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells; D002352:Carrier Proteins / Q000378:metabolism*; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects; D008745:Methylation; D015394:Molecular Structure; D000074011:Peptide Transporter 1; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism* / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D027981:Symporters
D002352:Carrier Proteins; D000074011:Peptide Transporter 1; D010455:Peptides; D011355:Prodrugs; C082186:SLC15A1 protein, human; D027981:Symporters