TY  - THES
T1  - Pharmacophore aided hit identification, structural optimization and biological evaluation of benzothiazole derivatives as new potent and selective non-steroidal inhibitors of 17beta-hydroxysteroid dehydrogenase type 1
T3  - PloSOne, DOI:10.1371/journal.pone.0029252 ; Journal of medicinal chemistry, DOI: 10.1021/jm201711b ; Journal of medicinal chemistry. - 52. 2009, 21, S. 6724–6743
A1  - Spadaro,Alessandro
Y1  - 2012/04/04
N2  - 17beta-Hydroxysteroid dehydrogenase 1 (17beta-HSD1) catalyzes the conversion of the weakly active estrone (E1) to the highly active estradiol (E2). Recently, 17β-HSD1 came into the focus of interest as a novel therapeutic target for the treatment of estrogen dependent diseases like breast cancer (BC) and endometriosis. Two new classes of non-steroidal 17beta-HSD1 inhibitors were designed and synthesized as potential therapeutics. The search started from the pharmacophore screening of in house library (molecules with MW < 350). The virtual hits were experimentally validated, and, finally, a new core structure ([5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-2-yl](3-hydroxyphenyl)methanone) with a moderate inhibitory activity for 17beta-HSD1 was identified. Rigidification of the flexible hydroxy ethyl chain led to a benzothiazole derivative which already showed high inhibitory potency towards the target enzyme. Further structural modifications - OH substitution pattern, addition and variation of small substituents on different position of the phenyl moiety – via the synthesis of 70 new compounds led the discovery of two new classes of potent 17beta-HSD1 inhibitors with IC50 values in the low nanomolar range. In order not to counteract the therapeutic efficacy of 17β-HSD1 inhibitors it is important that the compounds are selective towards 17β-HSD2 since this enzyme catalyses the reverse reaction (oxidation of E2 to E1) and furthermore to avoid intrinsic estrogenic and systemic effects, the inhibitors should not show affinity to the estrogen receptors alpha and beta. Besides an excellent selectivity over 17beta-HSD2 and the estrogen receptors (ERs) alpha and beta, the most promising compounds of this study showed good cell permeability (T47-D), fair metabolic stability in human liver microsomes and moderate hepatic CYP inhibition. High inhibitory potency and selectivity was also found towards marmoset monkey 17beta-HSD1 and 17beta-HSD2 indicating that these compounds are suitable for in vivo evaluation in this animal endometriosis model. In conclusion, the present thesis provides an extensive structure-activity study regarding 17beta-HSD1 inhibition which might be useful for the developement of a clinically applicable therapeutic for the treatment of estrogen-dependent diseases.
KW  - Hormon
KW  - Selektiver Östrogen-Rezeptor-Modulator
KW  - Thoraxkrebs
KW  - Endometriose
KW  - Endokrin wirksamer Stoff
KW  - Inhibitor
CY  - Saarbrücken
PB  - Universitäts- und Landesbibliothek
AD  - Postfach 151141, 66041 Saarbrücken
UR  - http://scidok.sulb.uni-saarland.de/volltexte/2012/4796
ER  -