Validation of 17beta-HSD2 inhibition as potential approach for the prevention of osteoporosis: comparison of in vivo efficacy and safety between a 17beta-HSD2 inhibitor and a specifically targeting bone 17beta-HSD2 inhibitor

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Cessation of ovarian estrogen production represents a major cause for osteoporotic changes in the bone of postmenopausal women. Maintenance of increased levels of estradiol (E2), the most potent estrogen locally in bone rather than systemically, is beneficial for the treatment and prevention of osteoporosis. It is the working hypothesis of this proposal that this could be achieved by 17beta-hydroxysteroid dehydrogenase type 2 (17beta-HSD2) inhibition. Potent and selective inhibitors of 17beta-HSD2 have already been described. This enzyme is expressed in bones and in other organs like breast and endometrium. Inhibition of 17beta-HSD2 will increase E2 levels locally in bones. However, due to the more general distribution of this enzyme, E2 levels will also be elevated in all tissues where the enzyme is expressed and therefore, theoretically, pose a risk for side-effects (breast cancer or endometrial hyperplasia). Bones have a high mineral content (hydroxyapatite), which make them specifically targetable by negatively charged substances. The goals of the proposed project are: 1. to optimize the structure of the 17beta-HSD2 inhibitors, by linking a bone carrier (bearing negative charges) to a previously described active 17beta-HSD2 inhibitor to assure bone specificity. The newly designed compound with bone carrier should be stable enough in plasma to stay intact for uptake onto bone and the carrier moiety should be cleaved in bone by endogenous esterases to liberate the active 17beta-HSD2 inhibitor, 2. to evaluate the efficacy of 2 compounds in vivo in a preventive setting using the castration-induced osteoporosis rat model. The compounds comprise a) an available, previously described active 17beta-HSD2 inhibitor without bone targeting carrier, as well as the same 17beta-HSD2 inhibitor with bone carrier, to be identified under point 1 and finally 3. to assess the safety aspect of this approach by analyzing critical tissues (mammary gland, endometrium) following administration of both inhibitors. As an outcome, we expect the validation of 17beta-HSD2 as promising target for the treatment and prevention of postmenopausal osteoporosis and the identification of potential drawbacks.