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6‐Hydroxybenzothiophene Ketones: Potent Inhibitors of 17β‐Hydroxysteroid Dehydrogenase Type 1 (17β‐HSD1) Owing to Favorable Molecule Geometry and Conformational Preorganization

The inhibition of 17β‐hydroxysteroid dehydrogenase type 1 (17β‐HSD1), which catalyzes the conversion of estrone into the potent estrogen receptor agonist estradiol (E2), is discussed as a novel therapeutic approach for the treatment of estrogen‐dependent diseases. Because the reduction of E2 would be basically limited to the target tissues, this approach is expected to cause fewer side effects than the currently employed antihormonal therapies. Recently, we reported on 6‐hydroxybenzothiazole ketones as a new class of 17β‐HSD1 inhibitors with a notable activity/selectivity profile. In an attempt to further optimize these parameters, we modified the benzothiazole core by a systematic bioisosteric replacement. Thus, we were able to identify a new 6‐hydroxybenzothiophene derivative that displayed stronger inhibition of 17β‐HSD1 (IC50=13 nM) and that was also more selective than a benzothiazole analog. Using ab initio calculations, we found that the higher potency of the 6‐hydroxybenzothiophene derivative was probably due to more favorable conformational preorganization of the scaffold for binding to the enzyme.