New Drug-Like Hydroxyphenylnaphthol Steroidomimetics As Potent and Selective 17β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors for the Treatment of Estrogen-Dependent Diseases

• Published in: Journal of medicinal chemistry Vol. 54; no. 2; pp. 534 - 547
• Main Authors: Marchais-Oberwinkler, Sandrine, Wetzel, Marie, Ziegler, Erika, Kruchten, Patricia, Werth, Ruth, Henn, Claudia, Hartmann, Rolf W, Frotscher, Martin
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 27.01.2011; Amer Chemical Soc
• Subjects: 17-Hydroxysteroid Dehydrogenases - antagonists & inhibitors; Administration, Oral; Animals; Biological Availability; Cell Line, Tumor; Cell Membrane Permeability; Cell-Free System; Chemistry, Medicinal; Estrogen Receptor alpha - metabolism; Estrogen Receptor beta - metabolism; Estrogens - physiology; Female; Humans; Life Sciences & Biomedicine; Liver - metabolism; Male; Microsomes - drug effects; Microsomes - enzymology; Molecular Mimicry; Naphthols - chemical synthesis; Naphthols - chemistry; Naphthols - pharmacology; Pharmacology & Pharmacy; Phenols - chemical synthesis; Phenols - chemistry; Phenols - pharmacology; Placenta - enzymology; Pregnancy; Rats; Rats, Sprague-Dawley; Rats, Wistar; Recombinant Proteins - antagonists & inhibitors; Science & Technology; Steroids - chemistry; Structure-Activity Relationship; DESIGN; STEROID-5-ALPHA-REDUCTASE TYPE-1; CRYSTAL-STRUCTURE; IN-VIVO; ESTRADIOL; BIOLOGICAL EVALUATION; 17-BETA-HSD TYPE-1; RECEPTOR-ALPHA; BREAST; NONSTEROIDAL INHIBITORS
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm1009082

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.