Design and synthesis of bone-selective osteogenic oxysterol-bisphosphonate analog

骨选择性成骨氧甾醇二膦酸酯类似物的设计与合成

基本信息

批准号：
8777032
负责人：
Frank Stappenbeck
金额：
$ 14.93万
依托单位：
MAX BIOPHARMA, INC.
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-03 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8777032
关键词：
Acids Adipocytes Adverse effects Affect Affinity Age Alendronate American Anabolic Agents Animal Model Animals Binding Blood Circulation Bone Density Bone Formation Stimulation Bone Growth Bone Marrow Bone Matrix Bone Resorption Bone Tissue Cholesterol Cholesterol Homeostasis Clinical Clinical Trials Complication Deposition Development Disease Dose Drug Delivery Systems Embryo Erinaceidae FDA approved Family Fibroblasts Forteo Fracture Future Grant Human Hydrolysis Hydroxyapatites In Vitro Injection of therapeutic agent Intervention Investigation Lead Marketing Mediating Mesenchymal Mesenchymal Stem Cells Minerals Modeling Morbidity - disease rate Oral Oryctolagus cuniculus Osteoblasts Osteogenesis Osteoporosis Patients Pharmaceutical Preparations Pharmacotherapy Phase Process Property Proteins Rattus Reporting Risk Safety Series Site Small Business Innovation Research Grant Stromal Cells Structure-Activity Relationship Teriparatide Therapeutic Effect Tissues Vertebral column age related aging population analog bisphosphonate bone bone loss cell type controlled release design economic cost immunogenic improved in vitro activity in vivo lipid biosynthesis mortality next generation novel novel strategies osteoblast differentiation osteogenic osteoprogenitor cell oxidation preclinical study public health relevance response skeletal smoothened signaling pathway socioeconomics treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Osteoporosis affects 10 million Americans and another 34 million are osteopenic and at risk for developing osteoporosis. Bone fractures, the most important complication of osteoporosis, cause substantial morbidity and mortality in the aging population as well as significant socio-economic cost. Since the 1960's, bisphosphonate drug therapy has produced modest clinical benefits such as improved bone density and reduced fracture risk by slowing osteoclastic bone resorption. To this date, all marketed therapies for osteoporosis as well as the majority of potential new treatments under clinical investigation aim to reduce the level of bone resorption in osteoporotic patients. Anti-resorptive drug therapy has been most effective in treating early and mild cases of the disease, unlike severe osteoporosis, where a massive loss of bone mineral density has already occurred. New strategies are urgently needed for intervention in osteoporosis, particularly in severe cases of the disease, including targeting mechanisms of bone formation that have previously been unexplored that can safely promote anabolic bone growth. Presently, there is only one FDA approved bone anabolic agent, Forteo (teriparatide) that confers significant clinical benefits in osteoporosis, but its use is severely restricted due to safety concerns. Multipotent mesenchymal stem cells (MSCs) are precursors of a variety of cell types, including osteoblasts and adipocytes. Formation of new bone is driven by osteoblastic differentiation of MSCs, a process that can be disrupted by age and other factors in favor of adipogenesis. Parhami et al. discovered that specific naturally-occurring oxysterols induce osteogenesis when applied to MSCs while inhibiting their adipogenesis. Recently, we have characterized a new series of semi-synthetic analogues of the natural oxysterols with improved properties. Our most advanced compound, OXY133, displays increased potency for osteogenic differentiation in vitro, and stimulates robust localized bone formation in vivo in a rat and rabbit spine fusion model. Here we propose to begin evaluating Oxy133 as a bone anabolic agent in the context of systemic administration and bone targeting by taking advantage of the well-known affinity of bisphosphonates for selectively binding to bone mineral. Our strategy involves conjugation of OXY133 to a known bisphosphonate, alendronic acid, which has previously been used as a bone targeting agent, using tunable linkers for controlled release. We predict that systemic dosing of such conjugates will result in their selective deposition in bone followed by enzymatic linker hydrolysis and release of the osteogenic agent, OXY133, at controlled rates into the bone tissue. We propose to perform studies as part of three Specific Aims that involve: 1) design & synthesis of Oxy133-bisphosphonate conjugated analogues, 2) examination of the hydroxyapatite binding capacity of these analogues, and 3) assessment of their osteogenic activity. Information obtained from these studies will provide the rationale for future investigation of the therapeutic effects of Oxy133-bisphosphonate analogues in animal models of osteoporosis.

描述（由申请人提供）：骨质疏松症影响着 1000 万美国人，另外 3400 万美国人骨质疏松，有患骨质疏松症的风险。骨折是骨质疏松症最重要的并发症，在老龄化人口中导致大量发病率和死亡率以及巨大的社会经济成本。自 20 世纪 60 年代以来，双膦酸盐药物治疗已经产生了一定的临床益处，例如通过减缓破骨细胞的骨吸收来改善骨密度并降低骨折风险。迄今为止，所有上市的骨质疏松症疗法以及临床研究中的大多数潜在新疗法都旨在降低骨质疏松症患者的骨吸收水平。抗骨吸收药物治疗对于治疗该疾病的早期和轻度病例最为有效，这与已经发生骨矿物质密度大量损失的严重骨质疏松症不同。迫切需要新的策略来干预骨质疏松症，特别是在该疾病的严重病例中，包括针对以前未被探索过的可安全促进合成代谢骨生长的骨形成机制。目前，只有一种 FDA 批准的骨合成代谢药物 Forteo（特立帕肽）对骨质疏松症具有显着的临床益处，但由于安全问题，其使用受到严格限制。多能间充质干细胞（MSC）是多种细胞类型的前体，包括成骨细胞和脂肪细胞。新骨的形成是由间充质干细胞的成骨细胞分化驱动的，这一过程可能会被年龄和其他有利于脂肪生成的因素所破坏。帕哈米等人。发现特定的天然存在的氧甾醇应用于间充质干细胞时会诱导成骨，同时抑制其脂肪生成。最近，我们表征了一系列具有改进性能的天然氧甾醇的新半合成类似物。我们最先进的化合物 OXY133 在体外显示出增强的成骨分化效力，并在大鼠和兔子脊柱融合模型中刺激体内稳健的局部骨形成。在这里，我们建议通过利用双膦酸盐选择性结合骨矿物质的众所周知的亲和力，开始在全身给药和骨靶向的背景下评估 Oxy133 作为骨合成代谢剂的作用。我们的策略涉及将 OXY133 与已知的双膦酸盐阿仑膦酸缀合，阿仑膦酸此前已被用作骨靶向剂，使用可调节连接体进行控制释放。我们预测，此类缀合物的全身给药将导致它们在骨中选择性沉积，随后酶促接头水解并以受控速率将成骨剂 OXY133 释放到骨组织中。我们建议将研究作为三个具体目标的一部分，包括：1）Oxy133-二膦酸酯缀合类似物的设计和合成，2）检查这些类似物的羟基磷灰石结合能力，以及3）评估其成骨活性。从这些研究中获得的信息将为未来研究 Oxy133-二膦酸盐类似物在骨质疏松症动物模型中的治疗效果提供依据。