Novel estrone mimetics with high 17beta-HSD1 inhibitory activity.
17Beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) catalyzes the reduction of estrone into estradiol, which is the most potent estrogen in humans. Lowering intracellular estradiol concentration by inhibition of this enzyme is a promising new option for the treatment of estrogen-dependent diseases like breast cancer and endometriosis. Combination of ligand- and structure-based design resulted in heterocyclic substituted biphenylols and their aza-analogs as new 17beta-HSD1 inhibitors. The design was based on mimicking estrone, especially focusing on the imitation of the D-ring keto group with (substituted) heterocycles. Molecular docking provided insights into plausible protein-ligand interactions for this class of compounds. The most promising compound 12 showed an inhibitory activity in the high nanomolar range and very low affinity for the estrogen receptors alpha and beta. Thus, compound 12 is a novel tool for the elucidation of the pharmacological relevance of 17beta-HSD1 and might be a lead for the treatment of estrogen-dependent diseases.
Oster
Alexander
A
Pharmaceutical and Medicinal Chemistry, Saarland University and Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), PO Box 15 11 50, D-66041 Saarbrücken, Germany.
Klein
Tobias
T
Werth
Ruth
R
Kruchten
Patricia
P
Bey
Emmanuel
E
Negri
Matthias
M
Marchais-Oberwinkler
Sandrine
S
Frotscher
Martin
M
Hartmann
Rolf W
RW
D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D032701:Biomimetics / Q000379:methods; D001943:Breast Neoplasms; D003198:Computer Simulation; D015195:Drug Design; D004958:Estradiol / Q000737:chemistry / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors; D004967:Estrogens / Q000737:chemistry / Q000494:pharmacology; D004970:Estrone / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D018931:Antineoplastic Agents, Hormonal; D047628:Estrogen Receptor alpha; D004967:Estrogens; D004970:Estrone; D004958:Estradiol; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase