Synthesis of bone-selective osteogenic oxysterols

骨选择性成骨氧甾醇的合成

基本信息

批准号：
8582074
负责人：
Frank Stappenbeck
金额：
$ 14.72万
依托单位：
MAX BIOPHARMA, 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：
2013-09-16 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8582074
关键词：
Adipocytes Adverse effects Affect Affinity Age American Anabolic Agents Animal Model Animals Anti-Bacterial Agents Antibiotics Area Aspartate Binding Blood Circulation Bone Density Bone Formation Stimulation Bone Growth Bone Marrow Bone Matrix Bone Resorption Bone Tissue Calvaria Cells Cholesterol Clinical Complication Conjugating Agent Defect Deposition Development Disease Dose Embryo Erinaceidae Esters Estradiol FDA approved Family Fibroblasts Forteo Fracture Future Grant Human Hydrolysis Hydroxyapatites In Vitro Injection of therapeutic agent Intervention Investigation Lead Link Mediating Medicine Mesenchymal Mesenchymal Stem Cells Minerals Modeling Morbidity - disease rate Mus Neonatal Oral Organ Culture Techniques Osteoblasts Osteoclasts Osteogenesis Osteoporosis Parents Patients Pharmaceutical Preparations Pharmacotherapy Phase Plague Positioning Attribute Process Property Rattus Reporting Risk Safety Series Site Small Business Innovation Research Grant Stromal Cells Structure-Activity Relationship Succinates Teriparatide Tetracyclines Therapeutic Agents Therapeutic Effect Therapeutic Intervention Tissues Tooth structure Vertebral column age related aging population analog base bisphosphonate bone bone healing bone loss cell type 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 therapy development

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 the disease, 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 clinical benefits such as improved bone density and reduced fracture risk by slowing osteoclastic bone resorption. The existing anti-resorptive drugs are plagued with untoward side effects and limited duration of clinical benefits. New and improved strategies for therapeutic intervention in osteoporosis are needed, particularly in the area of new medicines that 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, including in mouse and human primary MSCs, and it stimulates robust localized bone formation in vivo in a rat spine fusion model. Here we propose to begin evaluating Oxy133 as a bone anabolic agent in the context of systemic administration and bone targeting. Our strategy involves conjugation of OXY133 to a known bone-targeting agent (BTA) derived from tetracycline. 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 have produced the first example of such a conjugate, OXY149, and determined that it retains significant osteogenic activity in C3H10T1/2 cells. Expanding on this proof of principle study, we propose to conjugate the BTA-linker to OXY133 through tunable succinate and aspartate ester linkages in different positions of the molecule, likely to result in variable degrees of linker hydrolysis and bone affinity thus allowing for optimization of these properties. We propose to perform studies as part of three Specific Aims: 1) Synthesis of Oxy133-BTA conjugated analogues, 2) Examination of the hydroxyapatite binding capacity of Oxy133-BTA conjugated analogues, and 3) Examination of the osteogenic activity of Oxy133-BTA conjugated analogues. Information obtained from these studies will provide the rationale for future investigation of the therapeutic effects of Oxy133-BTA analogues in animal models of osteoporosis that may ultimately lead to the development of new bone anabolic agents fit for use in humans.

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。骨折是疾病中最重要的并发症，导致人口老龄化以及大量社会经济成本的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破骨骨骨吸收来产生临床益处，例如提高骨密度和骨折风险。现有的抗敏化药物困扰着副作用，临床益处的持续时间有限。需要新的和改进的策略在骨质疏松症中进行治疗，尤其是在新的领域安全促进合成代谢骨生长的药物。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。发现特异性天然发生的氧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显示出在体外（包括小鼠和人类原发性MSC）中成骨分化的效力，并且它刺激了大鼠脊柱融合模型中体内稳健的局部骨形成。在这里，我们建议在系统性给药和骨骼靶向的背景下开始评估Oxy133作为骨合成代谢剂。我们的策略涉及将Oxy133结合到源自四环素的已知骨靶向剂（BTA）。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。我们已经产生了这种结合物oxy149的第一个例子，并确定它在C3H10T1/2细胞中保留了显着的成骨活性。为了扩展这项原则研究的证明，我们建议通过可调的琥珀酸酯和天冬氨酸酯链接在分子的不同位置将BTA链链接到Oxy133，可能会导致链接的水解程度变化，从而允许这样做。用于优化这些属性。我们建议进行研究作为三个具体目的的一部分：1）OXY133-BTA共轭类似物的合成，2）检查Oxy133-BTA共偶联类似物的羟基磷灰石结合能力，以及3）检查了Oxy133-BTA Conjugated类似类似物的肌动症的检查。从这些研究中获得的信息将为未来研究oxy133-BTA类似物在骨质疏松症的动物模型中的治疗作用提供基本原理，这最终可能导致新的骨合成代谢剂的发展。