| 1. |
- Våbenø, Jon, et al.
(författare)
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Benzyl-5-[N-(tert-butoxycarbonyl)amino]-4-oxo-6-phenylhexanoate
- 2005
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Ingår i: Acta Crystallographica Section E-Structure Reports Online. ; 61
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Tidskriftsartikel (refereegranskat)abstract
- The title compound, C24H29NO5, the benzyl ester of the Phe-Gly dipeptidomimetic containing a ketomethylene motif, was synthesized from the readily available α,β-unsaturated γ-ketoester. The methylene group in the benzyl part of the molecule is disordered. There is an intermolecular N-H••• O hydrogen bond linking the molecules in the crystal structure.
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| 2. |
- Våbenø, Jon, et al.
(författare)
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Conformational restrictions in ligand binding to the human intestinal di-/tripeptide transporter: implications for design of hPEPT1 targeted prodrugs.
- 2005
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Ingår i: Bioorganic & medicinal chemistry. - : Elsevier BV. - 0968-0896. ; 13:6, s. 1977-88
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the present study was to develop a computational method aiding the design of dipeptidomimetic pro-moieties targeting the human intestinal di-/tripeptide transporter hPEPT1. First, the conformation in which substrates bind to hPEPT1 (the bioactive conformation) was identified by conformational analysis and 2D dihedral driving analysis of 15 hPEPT1 substrates, which suggested that psi(1) approximately 165 degrees , omega(1) approximately 180 degrees , and phi(2) approximately 280 degrees were descriptive of the bioactive conformation. Subsequently, the conformational energy required to change the peptide backbone conformation (DeltaE(bbone)) from the global energy minimum conformation to the identified bioactive conformation was calculated for 20 hPEPT1 targeted model prodrugs with known K(i) values. Quantitatively, an inverse linear relationship (r(2)=0.81, q(2)=0.80) was obtained between DeltaE(bbone) and log1/K(i), showing that DeltaE(bbone) contributes significantly to the experimentally observed affinity for hPEPT1 ligands. Qualitatively, the results revealed that compounds classified as high affinity ligands (K(i)<0.5 mM) all have a calculated DeltaE(bbone)<1 kcal/mol, whereas medium and low-affinity compounds (0.5 mM
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| 3. |
- Våbenø, Jon, et al.
(författare)
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Dipeptidomimetic ketomethylene isosteres as pro-moieties for drug transport via the human intestinal di-/tripeptide transporter hPEPT1: design, synthesis, stability, and biological investigations.
- 2004
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Ingår i: Journal of medicinal chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 47:19, s. 4755-65
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 4. |
- Våbenø, Jon, et al.
(författare)
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Phe-Gly dipeptidomimetics designed for the di-/tripeptide transporters PEPT1 and PEPT2: synthesis and biological investigations.
- 2004
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Ingår i: Journal of medicinal chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 47:4, s. 1060-9
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Tidskriftsartikel (refereegranskat)abstract
- A series of five Phe-Gly dipeptidomimetics containing different amide bond replacements have been synthesized in a facile way from the readily available unsaturated ketoester 1, and their affinities for the di-/tripeptide transporters hPEPT1 (Caco-2 cells) and rPEPT2 (SKPT cells) were tested. The compounds contained the amide bond isosteres ketomethylene (2a), (R)- and (S)-hydroxyethylidene (3a and 4a), and (R)- and (S)-hydroxyethylene (5a and 6a) to provide information on the conformational and stereochemical requirements for hPEPT1 and rPEPT2 affinity. The affinity studies showed that for rPEPT2 there is no significant difference in affinity between the ketomethylene isostere 2a and the natural substrate Phe-Gly (K(i) values of 18.8 and 14.6 microM, respectively). Also the affinities for hPEPT1 are in the same range (K(i) values of 0.40 and 0.20 mM, respectively). This corroborates earlier findings that the amide bond as such is not essential for binding to PEPTX, but the results also reveal possible differences in the binding of ketomethylene isosteres to hPEPT1 and rPEPT2. The trans-hydroxyethylidene and hydroxyethylene isosteres proved to be poor substrates for PEPTX. These results provide new information about the importance of flexibility and of the stereochemistry at the C(4)-position for this class of compounds. Furthermore, the intracellular uptake of 2a-4a in Caco-2 cells was investigated, showing a 3-fold reduction of the uptake of 2a in the presence of the competetive inhibitor Gly-Pro, indicating contribution from an active transport component. No active uptake of 3a and 4a was observed. Transepithelial transport studies also indicated active transport of 2a across Caco-2 monolayers.
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