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

卵巢雌激素分泌的停止是绝经后妇女骨质增生的主要原因。雌二醇（E2）是骨中局部而非全身最有效的雌激素，维持升高的水平有利于治疗和预防骨质疏松症。该提议的工作假设是，这可以通过17 β-羟基类固醇脱氢酶2型（17 β-HSD 2）抑制来实现。已经描述了17 β-HSD 2的有效和选择性抑制剂。这种酶在骨骼和其他器官如乳腺和子宫内膜中表达。抑制17 β-HSD 2会增加骨骼中局部的E2水平。然而，由于这种酶的更普遍的分布，E2水平也将在酶表达的所有组织中升高，因此，理论上，会产生副作用（乳腺癌或子宫内膜增生）的风险。骨骼具有高矿物质含量（羟基磷灰石），这使得它们特别容易被带负电荷的物质所攻击。该项目的目标是：1。通过将骨载体（带有负电荷）连接到先前描述的活性17 β-HSD 2抑制剂以确保骨特异性，来优化17 β-HSD 2抑制剂的结构。新设计的具有骨载体的化合物在血浆中应足够稳定以保持完整以被骨吸收，并且载体部分应在骨中被内源性酯酶裂解以释放活性17 β-HSD 2抑制剂，2。使用去势诱导的骨质疏松症大鼠模型在预防性环境中评价2种化合物的体内功效。所述化合物包含a）可获得的、先前描述的不含骨靶向载体的活性17 β-HSD 2抑制剂，以及相同的含骨载体的17 β-HSD 2抑制剂，将在第1点和最后3点下鉴定。通过分析两种抑制剂给药后的关键组织（乳腺、子宫内膜），评估该方法的安全性。作为一个结果，我们期望验证17 β-HSD 2作为治疗和预防绝经后骨质疏松症的有前途的目标，并确定潜在的缺点。

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.