Design, synthesis and biological evaluation of bis(hydroxyphenyl) azoles as potent and selective non-steroidal inhibitors of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) for the treatment of estrogen-dependent diseases

The 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) catalyses the reduction of the weakly active estrone (E1) into the most potent estrogen, 17β-estradiol (E2). E2 stimulates the growth of hormone-dependent diseases via activation of the estrogen receptors (ERs). 17β-HSD1 is often over-expressed in breast cancer cells. Thus, it is an attractive target for the treatment of mammary tumours. The combination of a ligand- and a structure-based drug design approach led to the identification of bis(hydroxyphenyl) azoles as potential inhibitors of 17β-HSD1. Different azoles and hydroxy substitution patterns were investigated. The compounds were evaluated for activity and selectivity with regard to 17β-HSD2, ERα and ERβ. The most potent compound is 3-[5-(4-hydroxyphenyl)-1,3-oxazol-2-yl]phenol (18, IC50 = 0.31 μM), showing very good selectivity, high cell permeability and medium CaCo-2 permeability.

A series of 19 azoles were synthesised and 17β-HSD1 inhibition determined. Compound 18 showed highest activity in cell free and T-47D assays, excellent selectivity towards 17β-HSD2, ERα and ERβ and medium CaCo-2 permeability.Figure optionsDownload as PowerPoint slide