title: New drug-like hydroxyphenylnaphthol steroidomimetics as potent and selective 17β-hydroxysteroid dehydrogenase type 1 inhibitors for the treatment of estrogen-dependent diseases.
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.
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2 3, D-66123 Saarbrücken, Germany.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Marchais-Oberwinkler
authors.forename: Marie
authors.initials: M
authors.lastname: Wetzel
authors.forename: Erika
authors.initials: E
authors.lastname: Ziegler
authors.forename: Patricia
authors.initials: P
authors.lastname: Kruchten
authors.forename: Ruth
authors.initials: R
authors.lastname: Werth
authors.forename: Claudia
authors.initials: C
authors.lastname: Henn
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
authors.forename: Martin
authors.initials: M
authors.lastname: Frotscher
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D002474:Cell-Free System; D047628:Estrogen Receptor alpha / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000378:metabolism; D004967:Estrogens / Q000502:physiology*; D005260:Female; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D018716:Molecular Mimicry; D009284:Naphthols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010636:Phenols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010920:Placenta / Q000201:enzymology; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013256:Steroids / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D009284:Naphthols; D010636:Phenols; D011994:Recombinant Proteins; D013256:Steroids; D015067:17-Hydroxysteroid Dehydrogenases