Estrone C15 derivatives--a new class of 17beta-hydroxysteroid dehydrogenase type 1 inhibitors

Lowering local estradiol concentration by inhibition of the estradiol-synthesizing enzyme 17beta-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 m...

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Published inMolecular and cellular endocrinology Vol. 301; no. 1-2; p. 216
Main Authors Messinger, Josef, Husen, Bettina, Koskimies, Pasi, Hirvelä, Leena, Kallio, Lila, Saarenketo, Pauli, Thole, Hubert
Format Journal Article
LanguageEnglish
Published Ireland 25.03.2009
Subjects
Animals
Binding Sites
Crystallography, X-Ray
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Estradiol - chemistry
Estradiol Dehydrogenases - antagonists & inhibitors
Estrone - analogs & derivatives
Estrone - chemistry
Estrone - pharmacology
Humans
Models, Molecular
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Summary:Lowering local estradiol concentration by inhibition of the estradiol-synthesizing enzyme 17beta-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 10nM and had no effect on the activity of recombinant human 17beta-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.
ISSN:0303-7207