Structure–activity study in the class of 6-(3′-hydroxyphenyl)naphthalenes leading to an optimization of a pharmacophore model for 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) inhibitors

17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) catalyzes the transformation of estrone (E1) into the most potent estrogen, estradiol (E2), which stimulates cell proliferation and decreases apoptosis. 17β-HSD1 is often strongly overexpressed in estrogen-dependent diseases (like breast cancer and endometriosis). Thus, this over expressed enzyme is a promising novel target for the development of selective inhibitors, which could be used as drugs for the treatment of these diseases.Using a structure- and ligand-based approach, a pharmacophore model was proposed and a new class of non-steroidal inhibitors of 17β-HSD1 was designed. Enzyme inhibition was evaluated in vitro using the human enzyme. After identification of the 6-(3′-hydroxyphenyl)-2-naphthol scaffold 1, the potency of this class of inhibitors was further improved by substitution of the 1-position of the naphthalene ring by a phenyl group (compound 18, IC50 = 20 nM). Compound 18 also showed a good selectivity toward 17β-HSD2 and the estrogen receptors α and β.