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）：骨质疏松症会影响1000万美国人，而另外3400万是骨质减少症，患有骨质疏松症的风险。骨折，是骨质疏松症的最重要并发症，导致人口老龄化以及重大的社会经济成本导致大量发病率和死亡率。自1960年代以来，双膦酸盐药物疗法已通过减慢整骨骨骨吸收来产生适度的临床益处，例如提高骨密度和骨折风险。到目前为止，所有针对骨质疏松症的销售疗法以及临床研究下的大多数潜在新疗法旨在降低骨质疏松患者的骨吸收水平。与严重的骨质疏松症不同，抗敏感性药物治疗在治疗早期和轻度病例中最有效，因为骨矿物质密度已经大大损失。干预骨质疏松症，尤其是在严重的疾病病例中，迫切需要新的策略，包括靶向以前无法探索的骨形成机制，这些机制可以安全地促进合成代谢的骨生长。目前，只有一个FDA批准的骨合代剂Forteo（Teriparatide）赋予骨质疏松症的临床益处，但由于安全问题，其使用受到严重限制。多态间充质干细胞（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MSC的成骨细胞分化驱动的，MSC的成骨细胞分化可能会因年龄和其他因素而有利于脂肪生成的过程。 Parhami等。发现特定的天然氧化甲醇在抑制其脂肪形成的同时诱导成骨。最近，我们表征了具有改善特性的天然氧甲醇的新系列半合成类似物。我们最先进的化合物OXY133显示了体外成骨分化的效力，并刺激大鼠和兔脊柱融合模型中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的众所周知的亲和力来选择性地结合骨矿物质，从而开始评估OXY133作为骨合成代谢剂作为骨合成代谢剂。我们的策略涉及将Oxy133偶联到已知的双膦酸盐Alendronic Acid，该甲酸以前已被用作骨靶向剂，使用可调连接器进行控制释放。我们预测，这种结合物的全身剂量将导致其在骨骼中的选择性沉积，然后以酶促连接器的水解和成骨剂的释放，以控制速率进入骨组织。我们建议将研究作为三个涉及的特定目的的一部分：1）氧气133-三膦酸盐共轭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，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133-双膦酸酯类似物在骨质疏松症动物模型中的治疗作用提供基本原理。