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

• 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
• 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

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1000万美国人，另有3400万人骨质减少，有发生骨质疏松症的风险。骨折是骨质疏松症最重要的并发症，在老龄化人口中造成大量的发病率和死亡率以及显著的社会经济成本。自20世纪60年代以来，双膦酸盐药物治疗已经产生了适度的临床益处，例如通过减缓骨吸收来改善骨密度和降低骨折风险。到目前为止，所有已上市的骨质疏松症治疗以及大多数临床研究中的潜在新治疗都旨在降低骨质疏松症患者的骨吸收水平。抗吸收药物治疗在治疗早期和轻度病例中最有效，不像严重的骨质疏松症，其中已经发生了大量的骨矿物质密度损失。迫切需要新的策略来干预骨质疏松症，特别是在这种疾病的严重病例中，包括以前未探索的骨形成机制，这些机制可以安全地促进合成代谢骨生长。目前，只有一种FDA批准的骨合成代谢剂，Forteo（特立哌酮），在骨质疏松症中具有显著的临床益处，但由于安全性问题，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MSC的成骨细胞分化驱动的，这一过程可以被年龄和其他有利于脂肪生成的因素破坏。Parhami等人发现，当应用于MSC时，特异性天然存在的氧固醇诱导骨生成，同时抑制其脂肪生成。最近，我们已经确定了一系列新的半合成类似物的天然氧化甾醇具有改进的性能。我们最先进的化合物OXY 133在体外表现出更强的成骨分化能力，并在大鼠和兔脊柱融合模型中刺激体内稳固的局部骨形成。在这里，我们建议开始评估作为骨合成代谢剂的背景下，全身给药和骨靶向利用众所周知的亲和力的双膦酸盐选择性binding to bone mineral. Our策略涉及共轭的OXY 133到一个已知的双膦酸盐，阿仑膦酸，这是以前被用作骨靶向剂，使用可调接头控制释放。我们预测，这种缀合物的全身给药将导致它们在骨中的选择性沉积，随后是酶促接头水解和成骨剂OXY 133以受控速率释放到骨组织中。我们建议作为三个特定目标的一部分进行研究，包括：1）Oxy 133-双膦酸盐结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，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Oxy 133-双膦酸盐类似物在骨质疏松症动物模型中的治疗作用提供依据。