Objekt-Metadaten

In vitro and in vivo characterization of small molecular inhibitors of the (pro)renin receptor ((P)RR) signal transduction pathway
Schrezenmeier, Eva

HaupttitelIn vitro and in vivo characterization of small molecular inhibitors of the (pro)renin receptor ((P)RR) signal transduction pathway
TitelvarianteIn vitro und in vivo Charakterisierung von niedermolekularen Inhibitoren des Renin/Prorenin-Rezeptor ((P)RR) Signaltransduktionsweges
AutorSchrezenmeier, Eva
Geburtsort: Ulm
GutachterN.N.
weitere GutachterN.N.
Freie Schlagwörterrenin receptor; prorenin; pharmacokinetic data; oncology; wnt; wnt signalling pathway
DDC610 Medizin und Gesundheit
ZusammenfassungThe (pro)renin receptor ((P)RR) plays a crucial role in the development of cardial and renal end-organ damage. Within an academic setting our group aimed to develop small molecular inhibitors of the (P)RR and therefore named renin/ prorenin receptor blockers (RERBs). In this thesis, the effects of two inhibitors of the (P)RR pathway was investigated: the V-ATPase (vacuolar adenosine triphosphatase) inhibitor bafilomycin and genistein which blocks the translocation of promyelocytic leukemia zinc finger (PLZF) to the nucleus. Bafilomycin reduces cell number in a dose dependent manner, genistein in contrast reduces cell number only in high concentrations. In the context of Wnt signalling bafilomycin represses Wnt3a-induced stimulation of axin2. After our group has performed a high-throughput screen for the identification of novel RERB compounds the microsomal stabilities of 121 compounds and the in vivo half-lives of 22 compounds have been determined. In vivo half-lives and predicted in vivo hepatic clearance were correlated showing r2 values of 0,31 for the rat and 0,27 for the human species.
Our data support that the (P)RR is a promising target for oncological indications. Pharmacokinetic data helped to identify drug candidates for future in vivo proof-of-concept animal experiments. The weak coefficients of determination of in vitro and in vivo pharmacokinetic data question the benefit of using microsomal stability as a tool to select compounds for further testing.
Dokumente
PDF-Datei von FUDISS_thesis_000000098490
Falls Ihr Browser eine Datei nicht öffnen kann, die Datei zuerst herunterladen und dann öffnen.
 
Seitenzahl27
Fachbereich/EinrichtungMedizinische Fakultät Charité - Universitätsmedizin Berlin
Erscheinungsjahr2015
Dokumententyp/-SammlungenDissertation
Medientyp/FormatText
SpracheEnglisch
Rechte Nutzungsbedingungen
Tag der Disputation27.02.2015
Erstellt am06.03.2015 - 12:27:36
Letzte Änderung06.03.2015 - 12:29:27
 
Statische URLhttp://edocs.fu-berlin.de/diss/receive/FUDISS_thesis_000000098490
URNurn:nbn:de:kobv:188-fudissthesis000000098490-9
Zugriffsstatistik
E-Mail-Adresseeva-vanessa.schrezenmeier@charite.de