First structure-activity relationship of 17<em>&beta;</em>-hydroxysteroid dehydrogenase type 14 nonsteroidal inhibitors and crystal structures in complex with the enzyme.

17&beta;-HSD14 belongs to the SDR family and oxidizes the hydroxyl group at position 17 of estradiol and 5-androstenediol using NAD+ as cofactor. The goal of this study was to identify and optimize 17&beta;-HSD14 nonsteroidal inhibitors as well as to disclose their structure-activity relationship. In a first screen, a library of 17&beta;-HSD1 and 17&beta;-HSD2 inhibitors, selected with respect to scaffold diversity, was tested for 17&beta;-HSD14 inhibition. The most interesting hit was taken as starting point for chemical modification applying a ligand-based approach. The designed compounds were synthesized and tested for 17&beta;-HSD14 inhibitory activity. The two best inhibitors identified in this study have a very high affinity to the enzyme with a Ki equal to 7 nM. The strong affinity of these inhibitors to the enzyme active site could be explained by crystallographic structure analysis, which highlighted the role of an extended H-bonding network in the stabilization process. The selectivity of the most potent compounds with respect to 17&beta;-HSD1 and 17&beta;-HSD2 is also addressed