Feasibility study of GGDPS inhibition for osteoporosis

GGDPS抑制骨质疏松症的可行性研究

基本信息

批准号：
8522844
负责人：
JEFFREY D NEIGHBORS
金额：
$ 16.31万
依托单位：
TERPENOID THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8522844
关键词：
Advanced Development Advocate Affect Affinity Anabolism Apoptosis Binding Biological Markers Biological Process Bone Matrix Bone Resorption Bone necrosis Bone remodeling Calcium Caring Cell Line Cells Characteristics Clinical Cultured Cells Cyclophosphamide Data Detection Development Disease Disease model Drug Kinetics Enzymes Europe Feasibility Studies Foundations Fracture Functional disorder Funding Goals Health Care Costs Human In Vitro International Intervention Isoprene Japan Jaw Kidney Lead Libraries Measurement Measures Mechanical Stress Mechanics Mediating Metabolism Modality Modeling New Agents Nitrogen Osteoblasts Osteocalcin Osteoclasts Osteocytes Osteoporosis Pathway interactions Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Phase Population Prevalence Process Production Protein Geranylgeranylation Public Health Quality of life Rattus Regulation Relative (related person)Resistance Series Small Business Innovation Research Grant Solutions Supplementation TRANCE protein Testing Therapeutic Toxic effect Vitamin D base bisphosphonate bone bone strength bone turnover cathepsin K clinical application farnesyltranstransferase geranylgeranyl diphosphate hydroxyl group in vitro Model in vitro activity in vivo in vivo Model inhibitor/antagonist isoprenoid novel patient population pharmacophore phase 1 study phase 2 study programs public health relevance skeletal small molecule small molecule libraries spine bone structure standard care

项目摘要

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.

描述（由申请人提供）：这些研究的目的是确定专有的黄烷基二磷酸合酶抑制剂（GGSIS）的功效，以抑制与当前标准药物相比，抑制破骨细胞介导的骨吸收。我们已经开发了一组含有异戊二烯亚结构的专有双膦酸盐，这些双膦酸盐在体外表现出高度有效和特定的GGSI活性。这些化合物不包含临床使用的当前双膦酸盐的羟基或氮亚结构。我们的GGSI是双膦酸盐发育中的重大进展，因为它们针对下游酶相对于临床双膦酸盐。我们认为，根据我们的初步研究的强度以及对这种疾病的额外治疗需求，有必要进一步发展新型GGSI用于治疗骨质疏松症的治疗方法，这代表了一个重大且不断增长的公共卫生问题。确实，据估计，到2025年，骨质疏松症将每年导致价值250亿美元的健康费用。在这里，我们提出了SBIR I期研究，以证明GGSI在骨质疏松症中的可行性在常用的大鼠模型中。该提案中描述的可行性研究提供了一种简化的方法，可以使用体外模型从图书馆识别最活跃的GGSI对骨吸收，并将这些活性化合物转变为骨吸收的体内模型。在特定目标中，我们将使用基于细胞的模型根据整骨细胞吸收活性和抑制成骨细胞细胞凋亡来确定化合物的优先级。然后，在特定目标二中，我们将在骨质疏松症的卵巢切除大鼠模型中使用最高优先级化合物，并将体外数据与骨强度的体内测量，机制参与的生物标志物，骨吸收的生物标记物，骨吸收生物标记物以及骨细胞凋亡的生物标记物相关联。这些目标共同为我们提供了更详细的IND促进研究的决定。