Feasibility study of GGDPS inhibition for osteoporosis

描述(由申请人提供)：这些研究的目标是确定专有香叶基香叶基二磷酸合成酶抑制剂(GGSI)与当前标准护理药物相比在抑制破骨细胞介导的骨吸收方面的有效性。我们已经开发了一组专有的含有异戊二烯亚结构的双膦酸盐，它们在体外显示出高度有效和特异的GGSI活性。这些化合物不含目前临床上使用的双膦酸类化合物的羟基或氮亚结构。我们的GGSI代表了双膦酸盐开发的重大进展，因为它们针对的是相对于临床双膦酸盐的下游酶。我们认为，基于我们的初步研究的力量和对这种疾病的持续的额外治疗的需要，有必要进一步开发我们用于治疗骨质疏松症的新型GGSI。这种疾病是一个重大的和日益严重的公共卫生问题。事实上，据估计，到2025年，骨质疏松症每年将导致价值250亿美元的医疗成本。在这里，我们建议进行SBIR第一阶段研究，以证明GGSI在一种常用的大鼠骨质疏松症模型中治疗骨质疏松的可行性。这项建议中描述的可行性研究提供了一种简化的方法，利用体外模型从我们的文库中鉴定对骨吸收最有效的GGSI，并将这些活性化合物转化为骨吸收的体内模型。在特定的目标一中，我们将使用基于细胞的模型来优先考虑基于破骨细胞吸收活性和抑制成骨细胞凋亡的化合物。然后，在特定的目标二中，我们将在去卵巢的大鼠骨质疏松模型中使用最优先的化合物，并将体外数据与体内骨强度测量、机制参与的生物标记物、骨吸收的生物标记物和成骨细胞凋亡的体外标记物相关联。综合起来，这些目标将为我们提供一个通过或不通过的决定，以便进行更详细的IND支持研究。

DESCRIPTION (provided by applicant): The goal of these studies is to determine the efficacy of proprietary geranylgeranyl diphosphate synthase inhibitors (GGSIs), for inhibition of osteoclast mediated bone resorption in comparison to current standard-of-care agents. We have developed a group of proprietary bisphosphonates containing isoprene substructures that demonstrate highly potent and specific GGSI activity in vitro. These compounds do not contain the hydroxyl group or the nitrogen substructure of the current bisphosphonates, which are used clinically. Our GGSIs represent a significant advance in bisphosphonate development in that they target a downstream enzyme relative to the clinical bisphosphonates. We feel that further development of our novel GGSIs for the treatment of osteoporosis is warranted based on the strength of our preliminary studies and the ongoing need for additional treatments for this disease which represents a significant and growing public health problem. Indeed, it is estimated that by 2025 osteoporosis will result in $25 billion worth of health costs each year. Here we propose SBIR Phase I studies to prove the feasibility of GGSIs in osteoporosis in a commonly used rat model of the disease. The feasibility studies described in this proposal provide a streamlined approach towards identification of the most active GGSI towards bone resorption from our library using in vitro models, and transition of these active compounds into an in vivo model of bone resorption. In specific aim one we will use cell based models to prioritize our compounds based on osteoclast resorption activity and inhibition of osteoblast apoptosis. Then in specific aim two we will use the highest priority compound in an ovariectomized rat model of osteoporosis and correlate the in vitro data to in vivo measurements of bone strength, biomarkers of mechanism engagement, biomarkers of bone resorption, and ex vivo markers of osteoblast apoptosis. Together these aims will provide us with a go or no-go decision for more elaborate IND enabling studies.