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

• Published in: European journal of medicinal chemistry 2012, Vol.47 (1), p.1-17
• Main Authors: Wetzel, Marie, Gargano, Emanuele M., Hinsberger, Stefan, Marchais-Oberwinkler, Sandrine, Hartmann, Rolf W.
• Format: Article
• Language: English
• Subjects: 17β-HSD2; Benzophenones - chemical synthesis; Benzophenones - chemistry; Benzophenones - pharmacology; Benzophenones - therapeutic use; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Drug Discovery; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Estradiol Dehydrogenases - antagonists & inhibitors; Inhibitory Concentration 50; Medical sciences; Models, Molecular; Molecular Conformation; Non steroidal inhibitors; Osteoporosis; Osteoporosis - drug therapy; Pharmacology. Drug treatments; Receptors, Estrogen - antagonists & inhibitors; Steroidomimetics
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2011.09.004

E2 deficiency in elderly people has directly an effect on the skeleton and can lead to osteoporosis. As 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD2) catalyses the conversion between active 17β-hydroxysteroid estradiol (E2) and testosterone (T) into their less active 17-ketosteroid and has been found in bones, 17β-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 17β-HSD2 inhibition and their selectivity toward 17β-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 IC 50 value in the low nanomolar range (101 nM) and a selectivity factor of 13 toward 17β-HSD1. These results make compound 12 an interesting candidate for further biological evaluation. Starting from nonselective compound B, potent and selective 17b-HSD2 inhibitors were obtained by structural modification. [Display omitted] ► A series of novel bicyclic hydroxyphenylmethanone derivatives were synthesised. ► Some of these new compounds exhibited good 17β-HSD2 inhibitory activity. ► The best result was obtained by compound 12 with IC 50 = 101 nM and selectivity factor toward 17β-HSD1 of 13.