New Drug-Like Hydroxyphenylnaphthol Steroidomimetics As Potent and Selective 17β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors for the Treatment of Estrogen-Dependent Diseases
Citations Over TimeTop 10% of 2010 papers
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.
Related Papers
- → Synthesis and Biological Evaluation of Spiro-δ-lactones as Inhibitors of 17β-Hydroxysteroid Dehydrogenase Type 2 (17β-HSD2)(2011)12 cited
- → Nad-dependent 3α- and 12α-hydroxysteroid dehydrogenase activities from eubacterwm lentum atcc no. 25559(1977)47 cited
- Serum lactate dehydrogenase, alpha-hydroxybutyrate dehydrogenase and ratio of alpha-hydroxybutyrate dehydrogenase to lactate dehydrogenase in testicular tumours.(1990)
- → Enzyme induction inStreptomyces hydrogenans. Comparison of the effects of different steroids to increase the activity of 3α, 20β-hydroxysteroid dehydrogenase and of 3β, 17β-hydroxysteroid dehydrogenase(1982)5 cited
- → Enzyme induction in Streptomyces hydrogenans. Comparison of the effects of different steroids to increase the activity of 3α, 20β‐hydroxysteroid dehydrogenase and of 3β, 17β‐hydroxysteroid dehydrogenase(1982)