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New drug-like hydroxyphenylnaphthol steroidomimetics as potent and selective 17β-hydroxysteroid dehydrogenase type 1 inhibitors for the treatment of estrogen-dependent diseases.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2011 Jan 27; Vol. 54 (2), pp. 534-47. Date of Electronic Publication: 2010 Dec 28. - Publication Year :
- 2011
-
Abstract
- Inhibition of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) is a novel and attractive approach to reduce the local levels of the active estrogen 17β-estradiol in patients with estrogen-dependent diseases like breast cancer or endometriosis. With the aim of optimizing the biological profile of 17β-HSD1 inhibitors from the hydroxyphenylnaphthol class, structural optimizations were performed at the 1-position of the naphthalene by introduction of different heteroaromatic rings as well as substituted phenyl groups. In the latter class of compounds, which were synthesized applying Suzuki-cross coupling, the 3-methanesulfonamide 15 turned out to be a highly potent 17β-HSD1 inhibitor (IC(50) = 15 nM in a cell-free assay). It was also very active in the cellular assay (T47D cells, IC(50) = 71 nM) and selective toward 17β-HSD2 and the estrogen receptors α and β. It showed a good membrane permeation and metabolic stability and was orally available in the rat.
- Subjects :
- Administration, Oral
Animals
Biological Availability
Cell Line, Tumor
Cell Membrane Permeability
Cell-Free System
Estrogen Receptor alpha metabolism
Estrogen Receptor beta metabolism
Female
Humans
Liver metabolism
Male
Microsomes drug effects
Microsomes enzymology
Molecular Mimicry
Naphthols chemistry
Naphthols pharmacology
Phenols chemistry
Phenols pharmacology
Placenta enzymology
Pregnancy
Rats
Rats, Sprague-Dawley
Rats, Wistar
Recombinant Proteins antagonists & inhibitors
Structure-Activity Relationship
17-Hydroxysteroid Dehydrogenases antagonists & inhibitors
Estrogens physiology
Naphthols chemical synthesis
Phenols chemical synthesis
Steroids chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 54
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 21189020
- Full Text :
- https://doi.org/10.1021/jm1009082