Sökning: onr:"swepub:oai:gup.ub.gu.se/54887" >
Dipeptidomimetic ke...
Dipeptidomimetic ketomethylene isosteres as pro-moieties for drug transport via the human intestinal di-/tripeptide transporter hPEPT1: design, synthesis, stability, and biological investigations.
-
Våbenø, Jon (författare)
-
Uhd Nielsen, Carsten (författare)
-
Ingebrigtsen, Truls (författare)
-
visa fler...
-
Lejon, Tore (författare)
-
Steffansen, Bente (författare)
-
- Luthman, Kristina, 1953 (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för kemi,Department of Chemistry
-
visa färre...
-
(creator_code:org_t)
- 2004-08-10
- 2004
- Engelska.
-
Ingår i: Journal of medicinal chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 47:19, s. 4755-65
- Relaterad länk:
-
https://gup.ub.gu.se...
-
visa fler...
-
https://doi.org/10.1...
-
visa färre...
Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medicinal Chemistry (hsv//eng)
Nyckelord
- Biological Transport
- drug effects
- Caco-2 Cells
- Carrier Proteins
- metabolism
- Drug Design
- Humans
- Inhibitory Concentration 50
- Intestines
- drug effects
- metabolism
- Methylation
- Molecular Structure
- Peptides
- chemistry
- metabolism
- Prodrugs
- chemical synthesis
- chemistry
- metabolism
- pharmacokinetics
- Structure-Activity Relationship
- Symporters
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
Hitta via bibliotek
Till lärosätets databas