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.

Metabolic stability optimization and metabolite identification of 2,5-thiophene amide 17β-hydroxysteroid dehydrogenase type 2 inhibitors

“…h17β-HSD2, h17β-HSD1, m17β-HSD2 and m17β-HSD1 cell-free assays were performed similarly, by incubating enzyme, tritiated substrate, cofactor and inhibitor, according to described procedures [20][21][22][23].…”

“…Cytosolic (h17β-HSD1) and microsomal (h17β-HSD2) fractions were obtained from human placenta according to previously described procedures [21,28]. Fresh tissue was homogenized and the enzymes were separated from the mitochondria, cell membrane.…”

“…The residue was purified by silica gel column chromatography (hexanes/EtOAc70:30) to afford the desired product as yellow solid (77 mg, 97 %). C 21 …”

“…The residue was purified by silica gel column chromatography (hexanes/EtOAc70:30) to afford the desired product as yellow solid (91 mg, 89 %). C 21 N-(3-methoxyphenyl)-N,3'-dimethyl-[1,1'-biphenyl]-4-carboxamide (6a) The title compound was prepared by reaction of 4-bromo-N-(3-methoxyphenyl)-N-methylbenzamide (6b) (77 mg, 0.24mmol), 3-methylphenylboronic acid (42 mg, 0.31mmol), cesium carbonate (235 mg, 0.72mmol) and tetrakistriphenylphosphine palladium (0.02 eq., 6 mg) in DME/EtOH/H 2 O (1/1/1/, 3 mL) according to method B. The residue was purified by silica gel column chromatography (hexanes/EtOAc70:30) to afford the desired product as colorless oil (56 mg, 71 %).…”

Towards the evaluation in an animal disease model: Fluorinated 17β-HSD1 inhibitors showing strong activity towards both the human and the rat enzyme

“…Starting point for the design was the class of bicyclic substituted hydroxyphenylmethanones (BSHs). [27][28][29] In contrast to most other classes of 17β-HSD1 inhibitors described by us [30][31][32][33][34][35][36][37][38], it contains members which not only are strong inhibitors of the human enzyme but also show inhibition of the murine ortholog (previously unpublished results, fig.2). Examples are compounds D and E ( fig.…”