Bicyclic substituted hydroxyphenylmethanones as novel inhibitors of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) for the treatment of estrogen-dependent diseases.
Estradiol (E2), the most important estrogen in humans, is involved in the initiation and progression of estrogen-dependent diseases such as breast cancer and endometriosis. Its local production in the target cell is regulated by 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1), which catalyzes E2-formation by reduction of the weak estrogen estrone (E1). Because the enzyme is expressed in the diseased tissues, inhibition of 17β-HSD1 is considered as a promising therapy for the treatment of estrogen-dependent diseases. For the development of novel inhibitors, a structure- and ligand-based design strategy was applied, resulting in bicyclic substituted hydroxyphenylmethanones. In vitro testing revealed high inhibitory potencies toward human placental 17β-HSD1. Compounds were further evaluated with regard to selectivity (17β-HSD2, estrogen receptors ERα and ERβ), intracellular activity (T47D cells), and metabolic stability. The most promising compounds, 14 and 15, showed IC(50) values in the low nanomolar range in the cell-free and cellular assays (8-27 nM), more than 30-fold selectivity toward 17β-HSD2 and no affinity toward the ERs. The data obtained make these inhibitors interesting candidates for further preclinical evaluation.
Pharmaceutical and Medicinal Chemistry, Saarland University, and Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Campus C23, D-66123 Saarbrücken, Germany.
Alexander
A
Oster
Stefan
S
Hinsberger
Ruth
R
Werth
Sandrine
S
Marchais-Oberwinkler
Martin
M
Frotscher
Rolf W
RW
Hartmann
D045744:Cell Line, Tumor; D015195:Drug Design; D004355:Drug Stability; D004960:Estradiol Dehydrogenases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D047628:Estrogen Receptor alpha / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000378:metabolism; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000378:metabolism; D010636:Phenols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D010636:Phenols; D013844:Thiazoles; D013876:Thiophenes; D004960:Estradiol Dehydrogenases; C513331:HSD17B1 protein, human; C523763:HSD17B2 protein, human