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

Abstract

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.

Estrogen and androgen-converting enzymes 17β-hydroxysteroid dehydrogenase and their involvement in cancer: with a special focus on 17β-hydroxysteroid dehydrogenase type 1, 2, and breast cancer

“…Several authors have proposed the use of HSD17B1 inhibitors for breast cancer, either as a single treatment, conceivably once resistance to aromatase inhibitors has arisen, or in combination with other treatments [46, 71, 72]. The primary result of such inhibition would be the reduction of E2 levels and increased DHT levels in the tissues that express HSD17B1 [39, 44–46], and as such, side effects should be more limited than current anti-hormonal treatments due to the limited tissue expression of HSD17B1 in placenta, ovary [6] and breast epithelium [35, 36].…”

Inhibitors of 17β-hydroxysteroid dehydrogenase type 1, 2 and 14: Structures, biological activities and future challenges

“…A systemic bioisosteric replacement of benzothiazole by other heterocycles resulted in the identification of potent and selective 17β-HSD1 inhibitors bearing a benzothiophene moiety. Compound 44 (figure 9) is more active towards the target enzyme and displayed better selectivity over 17β-HSD2 than its benzothiazole analog 42(Miralinaghi et al 2014).Thiophenepyrimidinones. Messinger et al identified 17β-HSD1 inhibitors by computer aided drug design starting from a unique nonsteroidal pyrimidinone core (structure 45, figure 10) by optimizing R1 and R2.…”

Towards the evaluation in an animal disease model: Fluorinated 17β-HSD1 inhibitors showing strong activity towards both the human and the rat enzyme

“…Starting point for the design was the class of bicyclic substituted hydroxyphenylmethanones (BSHs). [27][28][29] In contrast to most other classes of 17β-HSD1 inhibitors described by us [30][31][32][33][34][35][36][37][38], it contains members which not only are strong inhibitors of the human enzyme but also show inhibition of the murine ortholog (previously unpublished results, fig.2). Examples are compounds D and E ( fig.…”