Synthesis of bone-selective osteogenic oxysterols

骨选择性成骨氧甾醇的合成

• 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
• 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

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。骨折是该疾病最重要的并发症，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产生临床益处，例如通过减缓破骨细胞骨吸收来提高骨密度并降低骨折风险。现有的抗骨吸收药物存在不良副作用和临床获益持续时间有限的问题。需要新的和改进的骨质疏松症治疗干预策略，特别是在新的领域 安全促进骨合成代谢生长的药物。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（包括在小鼠和人类原代 MSC 中）显示出增强的成骨分化效力，并且在大鼠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 与已知的源自四环素的骨靶向剂 (BTA) 结合。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。我们已经生产了此类缀合物的第一个例子 OXY149，并确定它在 C3H10T1/2 细胞中保留了显着的成骨活性。扩展这一原理研究证明，我们建议通过分子不同位置的可调节琥珀酸酯和天冬氨酸酯键将 BTA 连接器与 OXY133 缀合，可能导致不同程度的连接器水解和骨亲和力，从而允许 用于优化这些属性。我们建议将研究作为三个具体目标的一部分：1) Oxy133-BTA 缀合类似物的合成，2) 检查 Oxy133-BTA 缀合类似物的羟基磷灰石结合能力，以及 3) 检查 Oxy133-BTA 缀合类似物的成骨活性。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动物模型中的治疗效果提供依据，这可能最终导致适合人类使用的新型骨合成代谢剂的开发。