Feasibility study of GGDPS inhibition for osteoporosis

GGDPS抑制骨质疏松症的可行性研究

• 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
• 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

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（由申请方提供）：这些研究的目的是确定专有香叶基香叶基二磷酸合酶抑制剂（GGSI）与当前标准治疗药物相比抑制破骨细胞介导的骨吸收的疗效。我们开发了一组专有的含有异戊二烯亚结构的双膦酸盐，其在体外表现出高度有效和特异性的GGSI活性。这些化合物不含羟基或目前临床使用的双膦酸盐的氮亚结构。我们的GGSI代表了双膦酸盐开发的重大进展，因为它们靶向相对于临床双膦酸盐的下游酶。我们认为，基于我们初步研究的优势和对这种疾病（代表一个重大且日益严重的公共卫生问题）的额外治疗的持续需求，进一步开发用于治疗骨质疏松症的新型GGSI是必要的。事实上，据估计，到2025年，骨质疏松症每年将导致价值250亿美元的医疗费用。在这里，我们提出SBIR I期研究，以证明GGSI在骨质疏松症的常用大鼠模型的可行性。 本提案中描述的可行性研究提供了一种简化的方法，用于使用体外模型从我们的库中鉴定对骨吸收最具活性的GGSI，并将这些活性化合物转化为体内骨吸收模型。在具体目标一中，我们将使用基于细胞的模型，基于破骨细胞再吸收活性和成骨细胞凋亡的抑制来优先考虑我们的化合物。然后，在具体目标二中，我们将在切除卵巢的骨质疏松症大鼠模型中使用最高优先级的化合物，并将体外数据与骨强度的体内测量、机制接合的生物标志物、骨吸收的生物标志物和成骨细胞凋亡的离体标志物相关联。这些目标将为我们提供一个进行或不进行更详细的IND使能研究的决定。