Phe-Gly Dipeptidomimetics Designed for the Di-/Tripeptide Transporters PEPT1 and PEPT2: Synthesis and Biological Investigations

Journal of Medicinal Chemistry

Volumn 47, Issue 4, 2004, Pages 1060-1069

  Våbenø, Jon ^a   Lejon, Tore ^a   Nielsen, Carsten Uhd ^b   Steffansen, Bente ^b   Chen, Weiqing ^c   Ouyang, Hui ^c   Borchardt, Ronald T ^c   Luthman, Kristina ^a,d  

^a UNIVERSITY OF TROMSØ   (Norway)

^b UNIVERSITY OF COPENHAGEN   (Denmark)

^c UNIVERSITY OF KANSAS   (United States)

^d UNIVERSITY OF GOTHENBURG   (Sweden)

Author keywords

[No Author keywords available]

Indexed keywords

5 AMINO 4 HYDROXY 6 PHENYL 2 HEXENOIC ACID; 5 AMINO 4 HYDROXY 6 PHENYLHEXANOIC ACID; 5 AMINO 4 OXO 6 PHENYLHEXANOIC ACID; AMIDE; DIPEPTIDE; GLYCINE; HYDROXYETHYLENE; HYDROXYETHYLIDENE; KETOMETHYLENE ISOSTERE; PEPTIDE TRANSPORTER 1; PEPTIDE TRANSPORTER 2; PHENYLALANINE; PRODRUG; PROLINE; UNCLASSIFIED DRUG;

ACTIVE TRANSPORT; ANIMAL CELL; ARTICLE; CHEMICAL BOND; CONFORMATION; DRUG PROTEIN BINDING; DRUG STRUCTURE; DRUG SYNTHESIS; DRUG UPTAKE; HUMAN; HUMAN CELL; NONHUMAN; PROTEIN BINDING; STEREOCHEMISTRY; STRUCTURE ANALYSIS;

ANIMALS; BIOLOGICAL TRANSPORT; CARRIER PROTEINS; CELL LINE; DIPEPTIDES; DRUG DESIGN; HEXANOIC ACIDS; HUMANS; MOLECULAR MIMICRY; OLIGOPEPTIDES; RATS; STRUCTURE-ACTIVITY RELATIONSHIP; SYMPORTERS;

EID: 0842304421     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm031022+     Document Type: Article

References (52)

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41. i values of Phe-Gly and Phe-Ala will be less pronounced in the Caco-2 assay (incubation time 5 min) than in the SKPT assay (incubation time 30 min). Regarding Gly-Pro, it has been used in several studies of PEPTX-mediated transport due to its relatively high stability (Ganapathy, V.; Mendicino, J.; Pashley, D. H.; Leibach, F. H. Carrier-mediated transport of glycyl-L-proline in renal brush border vesicles. Biochem. Biophys. Res. Commun. 1980, 97, 1133-1139).
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43. app is calculated from the linear part of the curve describing the amount of substrate transported as a function of time (eq 4) and is a steady-state value. In contrast, the apical uptake is not a steady-state value as such, since the uptake is measured under both pre-steady- and steady-state conditions (eq 3). However, the uptake experiments will still reflect the contribution from hPEPT1, and since this seems to be absent, the transepithelial transport (which suggests the contribution of hPEPT1) must be described by another mechanism.
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49. It should be mentioned that there is a possibility for the involvement of the peptide transporter 1 (hPT1) in the transport of dipeptidomimetics as suggested for valaciclovir (Landowski, C. P.; Sun, D.; Foster, D. R.; Menon, S. S.; Barnett, J. L.; Welage, L. S.; Ramachandran, C.; Amidon, G. L. Gene expression in the human intestine and correlation with oral valacyclovir pharmacokinetic parameters. J. Pharmacol. Exp. Ther. 2003, 306, 778-786); however, the role of hPT1 in transport of peptides and peptidomimetics is still not well understood.
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