Bicyclic Substituted Hydroxyphenylmethanone Type Inhibitors of 17 β‐Hydroxysteroid Dehydrogenase Type 1 (17 β‐HSD1): The Role of the Bicyclic Moiety

Abstract

An attractive target that has still to be explored for the treatment of estrogen-dependent diseases, such as breast cancer and endometriosis, is the enzyme responsible for the last step in the biosynthesis of estradiol (E2): 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1). It catalyzes the reduction of the weakly active estrone (E1) into E2, which is the most potent estrogen in humans. Inhibition of 17β-HSD1 lowers intracellular E2 concentrations and thus presents a therapeutic target for estrogen-dependent pathologies. Recently, we reported a new class of highly active and selective 17β-HSD1 inhibitors: bicyclic substituted hydroxyphenylmethanones. Here, further structural variations on the bicyclic moiety are described, especially focusing on the exchange of its hydroxy function. Twenty-nine novel inhibitors were synthesized and evaluated for 17β-HSD1 inhibition in a cell-free and cellular assay, for selectivity toward 17βHSD2 and estrogen receptors (ER) alpha and beta, as well as for metabolic stability. The best compound exhibited IC50 values of 12 nM (cell-free assay) and 78 nM (cellular assay), high selectivity for 17β-HSD1, and reasonable metabolic stability. A molecular docking study provided insight into the protein-ligand interactions of this compound with 17β-HSD1.

Inhibition of 17β-HSD1: SAR of bicyclic substituted hydroxyphenylmethanones and discovery of new potent inhibitors with thioether linker

“…[30,32] One of the structural features under investigation was the phenolic OH-group at the benzoyl moiety (ring A) of inhibitors A and B It was replaced with substituents which covered a broad spectrum of lipophilic and electronic properties and differed in their abilities to form hydrogen bond interactions with the target. The introduction of chlorine appeared interesting to us as it is known that this substituent, due to its σ-hole property, is able to replace classical donors like OH in H-bonding interactions.…”

“…Both steroidal [18,19] and non-steroidal [20][21][22][23][24][25][26][27][28][29][30][31] 17β-HSD1 inhibitors have been described in the past. Recently we reported on bicyclic substituted hydroxyphenylmethanones [32] (general structure, fig.…”

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.…”

“…2). [27,28] Drug design was focused on compound E as a lead and included structural variations with the aim of enhancing inhibitory activity towards rodent 17β-HSD1 while maintaining activity towards the human enzyme. …”

“…2). Thus, the aromatic sulfonamide moiety in combination with the BSH scaffold not only leads to a favourable activity profile against human 17β-HSD1 and 2 [28], but it also appears to be attractive in terms of activity against murine 17β-HSD1.…”