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

• Published in: Molecular and cellular endocrinology 2009-03, Vol.301 (1), p.205-211
• Main Authors: Marchais-Oberwinkler, Sandrine, Frotscher, Martin, Ziegler, Erika, Werth, Ruth, Kruchten, Patricia, Messinger, Josef, Thole, Hubert, Hartmann, Rolf W.
• Format: Article
• Language: English
• Subjects: 17β-HSD1; 17β-HSD2; Beta; Cellular; Diseases; Enzymes; Estrogen-dependent diseases; Estrogens; Inhibitors; Naphthalene; Non-steroidal inhibitor; Pharmacophore model; Phenyls
• ISSN: 0303-7207; 1872-8057; 0303-7207
• DOI: 10.1016/j.mce.2008.09.024

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, IC 50 = 20 nM). Compound 18 also showed a good selectivity toward 17β-HSD2 and the estrogen receptors α and β.