Lowering local estradiol concentration by inhibition of the 
estradiol-synthesizing enzyme 17beta-hydroxysteroid dehydrogenase type 1 
(17beta-HSD1) has been proposed as a promising new therapeutic option to treat 
estrogen-dependent diseases like endometriosis and breast cancer. Based on a 
molecular modelling approach we designed and synthesized novel C15-substituted 
estrone derivatives. Subsequent biological evaluation revealed that potent 
inhibitors of human 17beta-HSD1 can be identified in this compound class. The 
best, compound 21, inhibited recombinant human 17beta-HSD1 with an IC50 of 10nM 
and had no effect on the activity of recombinant human 17beta-hydroxysteroid 
dehydrogenase type 2 (17beta-HSD2), the enzyme catalyzing estradiol 
inactivation. These properties were retained in a cell-based enzyme activity 
assays. In spite of the estrogen backbone compound 21 did not show estrogen 
receptor mediated effects in vitro or in vivo. In conclusion, estrone C15 
derivative compound 21 can be regarded as a promising lead compound for further 
development as a 17beta-HSD1 inhibitor.