TY  - THES
T1  - Development of potent and selective inhibitors of 17β-hydroxysteroid dehydrogenase type 2 : a new target for the treatment of osteoporosis
A1  - Wetzel,Marie
Y1  - 2012/07/27
N2  - Using a ligand-based approach, we designed and synthesised novel non-steroidal 17beta-HSD2 inhibitors from two scaffolds described in literature as potential drugs for the treatment of osteoporosis. These compounds bear a hydrophobic core and two polar moieties, distant from each other circa 11Å, mimicking the two hydroxy group at the C3 and C17 position of the steroid E2. The best OH-OH substitution pattern was first elucidated in an optimisation process. Addition of further substituents to the best scaffold was investigated to enhance its activity and selectivity. Most of the synthesised compounds are potent 17β-HSD2 inhibitors with IC50 values in the low nanomolar range. Besides an outstanding selectivity towards 17β-HSD1 and a negligible affinity to the ERα and ERβ, the most promising compound of this thesis (II.19) displays high selectivity towards 17β-HSD4 and 17β-HSD5. It exhibits also good cell permeability in MDA-MB-231 cells, expressing naturally 17β-HSD2 and an excellent activity in rat, mouse and monkey enzymes. To conclude, the present work presents a broad SAR study of two classes of compounds regarding 17β-HSD2 inhibition and all of these results helped to generate a good homology model of the protein with the goal to better understand how potential drug binds in the enzymatic pocket.
KW  - Osteoporose
KW  - Inhibitor
KW  - Hydroxysteroid-Dehydrogenasen
CY  - Saarbrücken
PB  - Universitäts- und Landesbibliothek
AD  - Postfach 151141, 66041 Saarbrücken
UR  - http://scidok.sulb.uni-saarland.de/volltexte/2012/4909
ER  -