Discovery of a new class of bicyclic substituted hydroxyphenylmethanones as 17 beta-hydroxysteroid dehydrogenase type 2 (17 beta-HSD2) inhibitors for the treatment of osteoporosis

作者：Wetzel Marie; Gargano Emanuele M; Hin**erger Stefan; Marchais Oberwinkler Sandrine; Hartmann Rolf W^*

来源：European Journal of Medicinal Chemistry, 2012, 47: 1-17.

DOI：10.1016/j.ejmech.2011.09.004

• 17 beta-HSD2
• Osteoporosis
• Non steroidal inhibitors
• Steroidomimetics

E2 deficiency in elderly people has directly an effect on the skeleton and can lead to osteoporosis. As 17 beta-hydroxysteroid dehydrogenase type 2 (17 beta-HSD2) catalyses the conversion between active 17 beta-hydroxysteroid estradiol (E2) and testosterone (T) into their less active 17-ketosteroid and has been found in bones, 17 beta-HSD2 inhibitor may provide a new approach in the onset of osteoporosis. Bicyclic substituted hydroxyphenylmethanone derivatives were synthesised as steroidomimetics of the substrate E2 and were evaluated for their 17 beta-HSD2 inhibition and their selectivity toward 17 beta-HSD1, catalysing the reverse reaction the conversion of estrone (E1) into E2. Highly selective compounds (11, 12, 14, 21 and 22) have been identified, the most promising one (12) showing an IC50 value in the low nanomolar range (101 nM) and a selectivity factor of 13 toward 17 beta-HSD1. These results make compound 12 an interesting candidate for further biological evaluation.

• 出版日期2012-1