Novel estrone mimetics with high 17β-HSD1 inhibitory activity

17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) catalyzes the reduction of estrone into estradiol, which is the most potent estrogen in humans. Lowering intracellular estradiol concentration by inhibition of this enzyme is a promising new option for the treatment of estrogen-dependent diseases like breast cancer and endometriosis. Combination of ligand- and structure-based design resulted in heterocyclic substituted biphenylols and their aza-analogs as new 17β-HSD1 inhibitors. The design was based on mimicking estrone, especially focusing on the imitation of the D-ring keto group with (substituted) heterocycles. Molecular docking provided insights into plausible protein–ligand interactions for this class of compounds. The most promising compound 12 showed an inhibitory activity in the high nanomolar range and very low affinity for the estrogen receptors α and β. Thus, compound 12 is a novel tool for the elucidation of the pharmacological relevance of 17β-HSD1 and might be a lead for the treatment of estrogen-dependent diseases.

Estrone mimetics were synthesized and 17β-HSD1 inhibition was determined. Compound 12 showed high inhibitory activity, selectivity toward 17β-HSD2, ERα/ERβ and its binding mode shed light on a subpocket as interacting area.Figure optionsDownload as PowerPoint slide