1041114-10-6Relevant articles and documents
New drug-like hydroxyphenylnaphthol steroidomimetics as potent and selective 17β-hydroxysteroid dehydrogenase type 1 inhibitors for the treatment of estrogen-dependent diseases
Marchais-Oberwinkler, Sandrine,Wetzel, Marie,Ziegler, Erika,Kruchten, Patricia,Werth, Ruth,Henn, Claudia,Hartmann, Rolf W.,Frotscher, Martin
experimental part, p. 534 - 547 (2011/03/21)
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 (IC50 = 15 nM in a cell-free assay). It was also very active in the cellular assay (T47D cells, IC50 = 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.
Substituted 6-phenyl-2-naphthols. Potent and selective nonsteroidal inhibitors of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1): Design, synthesis, biological evaluation, and pharmacokinetics
Marchais-Oberwinkler, Sandrine,Krachten, Patricia,Frotscher, Martin,Ziegler, Erika,Neugebauer, Alexander,Bhoga, Umadevi,Bey, Emmanuel,Müller-Vieira, Ursula,Messinger, Josef,Thole, Hubert,Hartmann, Rolf W.
supporting information; experimental part, p. 4685 - 4698 (2009/07/19)
17β-Estradiol (E2) is implicated in the genesis and the development of estrogen-dependent diseases. Its concentration is mainly regulated by 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1), which catalyzes the reduction of the weak estrogen estrone (E1) to the highly potent E2. This enzyme is thus an important target for the treatment of hormone-dependent diseases. Thirty-seven novel substituted 6-phenyl-2-naphthols were synthesized and evaluated for 17β-HSD1 inhibition, selectivity toward 17β-HSD2 and the estrogen receptors (ERs) α and β, and pharmacokinetic properties. SAR studies revealed that the compounds most likely bind according to binding mode B to the active site, i.e., the 6-phenyl moiety mimicking the steroidal A-ring. While substitution at the phenyl ring decreased activity, introduction of substituents at the naphthol moiety led to highly active compounds, especially in position 1. The 1-phenyl compound 32 showed a very high inhibitory activity for 17β-HSD1 (IC50 = 20 nM) and good selectivity (17β-HSD2 and ERs) and pharmacokinetic properties after peroral application.
