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 17 beta-hydroxysteroid dehydrogenase type 1 (17 beta-HSD1) catalyses the reduction of the weakly active estrone (E1) into the most potent estrogen, 17 beta-estradiol (E2). E2 stimulates the growth of hormone-dependent diseases via activation of the estrogen receptors (ERs). 17 beta-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 17 beta-HSD1. Different azoles and hydroxy substitution patterns were investigated. The compounds were evaluated for activity and selectivity with regard to 17 beta-HSD2, ER alpha and ER beta. The most potent compound is 3-[ 5-(4-hydroxyphenyl)-1,3-oxazol-2-yl] phenol (18, IC50 = 0.31 mu M), showing very good selectivity, high cell permeability and medium CaCo-2 permeability. (c) 2008 Elsevier Ltd. All rights reserved.