NOVEL ADENOSINE A2A AGONISTS IN VASCULAR PROTECTION

血管干预后的再狭窄是由新生内膜增生和/或几何重塑引起的。然而，血管损伤后的早期反应尚不清楚。粘附分子的上调和白细胞的募集和激活似乎是重要的事件。腺苷调节血管损伤后的炎症反应，其中许多作用是由A2A受体介导的。我们已经证明，在小鼠颈动脉结扎后，给予特异性A2A受体激动剂DWH-146e 7天可减少新内膜形成和白细胞募集。然而，治疗的最佳持续时间是未知的，理想的药物应该有很长的作用时间。因此，本提案的目的1是确定A2A激动剂DWH146e的最佳治疗窗口，以最大限度地减少血管损伤后的新生内膜生长。目的二是合成并评价一种新的高效、稳定、长效的A2A受体激动剂，以最大限度地保护血管。我们已经开发了一种方案，以有效地合成腺苷类似物，是A2A腺苷受体的强效和高选择性激动剂。我们计划通过生物测定和化学检测方法鉴定在动物体内积累的代谢物。这项工作将由Adenosine Therapeutics， LLC完成。拟议的商业应用：我们建议合成，表征和商业化新型腺苷A2A激动剂，以减少血管损伤的新内膜反应。再狭窄仍然是血管干预后的一个重要问题，发生在20- 40%的病例中。我们激动人心的初步数据提出了一个显著限制这一过程的策略。我们预计这些研究将为血管损伤后炎症的作用提供重要的见解。这项工作可能在提高血管成形术的有效性、降低发病率和限制动脉粥样硬化性血管疾病的总成本方面具有相当大的临床影响。

Restenosis following vascular interventions results from neointimal hyperplasia and/or geometric remodeling. However, the early response following vascular injury is not well understood. Up-regulation of adhesion molecules and leukocyte recruitment and activation appear to be important events. Adenosine modulates the inflammatory response following vascular injury and many of these effects are mediated by the A2A receptor. We have demonstrated that a 7 day administration of the specific A2A receptor agonist DWH-146e decreases neointimal formation and leukocyte recruitment following carotid ligation in the mouse. However, the optimal duration of therapy is not known and an ideal drug would have a long duration of action. Accordingly, Aim 1 of this proposal is to determine the optimal therapeutic window for administration of the A2A agonist, DWH146e, to produce maximal reduction in neointimal growth after vascular injury. Aim 2 is to synthesize and evaluate a new potent, stable and long acting specific A2A agonist for maximal vascular protection. We have developed a scheme to efficiently synthesize adenosine analogs that are potent and highly selective agonists of A2A adenosine receptors. We plan to identify the metabolites that accumulate in animals by using bioassays and chemical detection methods. This work will be done by Adenosine Therapeutics, LLC. PROPOSED COMMERCIAL APPLICATIONS: We propose to synthesize, characterize and commercialize novel adenosine A2A agonists in order to reduce the neointimal response to vascular injury. Restenosis remains a significant problem after vascular interventions, occurring in 20-40 % of cases. Our exciting preliminary data suggests a strategy to significantly limit this process. We anticipate that these studies will provide important insights into the role of inflammation after vascular injury. This work may have considerable clinical impact with respect to enhancing the effectiveness of angioplasty, reducing morbidity and limiting the overall cost of atherosclerotic vascular disease.