Development of 3-substituted-androsterone derivatives as potent inhibitors of 17 beta-hydroxysteroid dehydrogenase type 3

作者：Maltais Rene; Fournier Michelle Audrey; Poirier Donald^*

来源：Bioorganic & Medicinal Chemistry, 2011, 19(15): 4652-4668.

DOI：10.1016/j.bmc.2011.06.003

• Steroid
• Androsterone
• Enzyme
• Hydroxysteroid dehydrogenase
• Cancer
• Androgen
• Hormone

17Beta-hydroxysteroid dehydrogenase type 3 (17 beta-HSD3) is a steroidogenic enzyme that catalyzes the transformation of 4-androstene-3,17-dione (Delta(4)-dione) into androgen testosterone (T). To provide effective inhibitors of androgen biosynthesis, we synthesized two different series (amines and carbamates) of 3 beta-substituted-androsterone derivatives and we tested their inhibitory activity on 17 beta-HSD3. From the results of our structure-activity relationship study, we identified a series of compounds producing a strong inhibition of 17 beta-HSD3 overexpressed in HEK-293 cells (homogenized cells). The most active compound when tested in intact HEK-293 transfected cells, namely (3 alpha,5 alpha)-3-{[trans-2,5-dimethyl-4-{[2-(trifluoromethyl)phenyl] sulfonyl}piperazin-1-yl]methyl}-3-hydroxyandrostan-17-one (15b), shows an IC50 value of 6 nM, this compound is thus eight times more active than our reference compound D-5-2 (IC50 = 51 nM). This new improved inhibitor did not stimulate the proliferation of androgen-sensitive Shionogi cells, suggesting a non-androgenic profile. Compound 15b is thus a good candidate for further in vivo studies on rodents.

• 出版日期2011-8