Estrone C15 derivatives—A new class of 17β-hydroxysteroid dehydrogenase type 1 inhibitors

• Published in: Molecular and cellular endocrinology 2009-03, Vol.301 (1), p.216-224
• Main Authors: Messinger, Josef, Husen, Bettina, Koskimies, Pasi, Hirvelä, Leena, Kallio, Lila, Saarenketo, Pauli, Thole, Hubert
• Format: Article
• Language: English
• Subjects: 17β-Hydroxysteroid dehydrogenase; Backbone; Cellular; Derivatives; Enzymes; Estrogen; Estrogens; Estrone; Human; Inhibitor; Inhibitors; Recombinant
• ISSN: 0303-7207; 1872-8057; 0303-7207
• DOI: 10.1016/j.mce.2008.10.022

Lowering local estradiol concentration by inhibition of the estradiol-synthesizing enzyme 17β-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) has been proposed as a promising new therapeutic option to treat estrogen-dependent diseases like endometriosis and breast cancer. Based on a molecular modelling approach we designed and synthesized novel C15-substituted estrone derivatives. Subsequent biological evaluation revealed that potent inhibitors of human 17beta-HSD1 can be identified in this compound class. The best, compound 21, inhibited recombinant human 17beta-HSD1 with an IC50 of 10 nM and had no effect on the activity of recombinant human 17β-hydroxysteroid dehydrogenase type 2 (17beta-HSD2), the enzyme catalyzing estradiol inactivation. These properties were retained in a cell-based enzyme activity assays. In spite of the estrogen backbone compound 21 did not show estrogen receptor mediated effects in vitro or in vivo. In conclusion, estrone C15 derivative compound 21 can be regarded as a promising lead compound for further development as a 17beta-HSD1 inhibitor.