New inhibitors of 17β-hydroxysteroid dehydrogenase type 1

The estradiol-synthesizing enzyme 17β-hydroxysteroid dehydrogenase type 1 (17βHSD1) is mainly responsible for the conversion of estrone (E1) to the potent estrogen estradiol (E2). It is a key player to control tissue levels of E2 and is therefore an attractive target in estradiol-dependent diseases like breast cancer or endometriosis.We selected a unique non-steroidal pyrimidinone core to start a lead optimization program. We optimized this core by modulation of R1–R6. Its binding mode at the substrate-binding site of 17βHSD1 is complex and difficult to predict. Nevertheless, some basic structure–activity relationships could be identified. In vitro, the most active pyrimidinone derivative showed effective inhibition of recombinant human 17βHSD1 at nanomolar concentrations. In intact cells overexpressing the human enzyme, IC50 values in the lower micromolar range were determined. Furthermore, the pyrimidinone proved its use in vivo by significantly reducing 17βHSD1-dependent tumor growth in a new nude mouse model.