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J Med Chem. 2016 Dec 8;59(23):10719-10737. Epub 2016 Nov 18.

First Structure-Activity Relationship of 17β-Hydroxysteroid Dehydrogenase Type 14 Nonsteroidal Inhibitors and Crystal Structures in Complex with the Enzyme.

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Institute for Pharmaceutical Chemistry, Philipps University Marburg , Marbacher Weg 6, 35032 Marburg, Germany.
Genome Analysis Center, Institute of Experimental Genetics, German Research Center for Environmental Health, Helmholtz Zentrum München , 85764 Neuherberg, Germany.
Chair of Experimental Genetics, Technical University Munich , 85350 Freising-Weihenstephan, Germany.
German Center for Diabetes Research (DZD) , 85764 Neuherberg, Germany.
ElexoPharm GmbH , Campus A1.2, 66123 Saarbrücken, Germany.


17β-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 17β-HSD14 nonsteroidal inhibitors as well as to disclose their structure-activity relationship. In a first screen, a library of 17β-HSD1 and 17β-HSD2 inhibitors, selected with respect to scaffold diversity, was tested for 17β-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 17β-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 17β-HSD1 and 17β-HSD2 is also addressed.

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