Background

17β hydroxysteroid dehydrogenase type 2 (17β-HSD2) catalyzes in vivo the oxidation of the highly potent estrogens like estradiol (E2) and androgens like testosterone (T) into their less active forms estrone (E1) and androstenedione (A-dione) respectively using the cofactor NAD+. Estrogen deficiency or down regulation in the bone cells is believed to be an important risk factor for osteoporosis. e.g. after menopauses or after treatment with aromatase inhibitors, which radically prevent estrogens biosynthesis. There are also substantial evidences that androgens like testosterone are involved in bone formation and may protect the bones against osteoporosis. A controlled increase of estradiol and testosterone in bones of osteoporotic patients will certainly reduce osteoporotic fractures and slow down bone loss by lowering bone resorption and by raising bone formation. A current intensively investigated approach for the treatment or prophylaxis of estrogen or androgen deficiency or down regulation is the development of inhibitors of 17β-HSD2. To date only very few 17β-HSD2 inhibitors are published. The main drawback of the known steroidal inhibitors is the lack of selectivity due to the residual estrogenic and androgenic activity which arises from their steroid nucleus.

Invention and Application

Scientists of Saarland University have recently succeeded in developing an improved series of new non-steroidal inhibitors of 17β-HSD2. Since 17β-HSD2 is regulating the level in potent estradiol and testosterone in the target tissues it is believed that inhibition of 17β-HSD2 can lead to an increase in steroid hormones. The newly synthesized inhibitors show a high potency at the protein level, i.e.

• 17β-HSD2: IC50 < 100 nM;
• Selectivity factor over 17β-HSD1 of up > 100;
• Very weak binding affinity to the estrogen receptors α and β: % RBA < 0.1;
• Good cellular activity (MDA-MB-231 cells)

Advantages

The presented compounds are selective non-steroidal inhibitors of 17β-HSD2. In their selectivity, they can considerably overmatch the established agents. Due to their low half maximal inhibitory concentration (IC50) and high selectivity it should be possible to use these inhibitors in order to develop substantially better treatment and prophylaxis for diseases caused by a deficient estrogen or androgen level (e.g. osteoporosis, neuronal diseases, rheumatic diseases, inflammatory diseases).