A2a Adenosine Agonists as Neuroprotectants

描述(由申请人提供)：本研究的中心目标是 开发预防继发性脊髓再灌注损伤的新药 胸外科手术中常见的主动脉阻断。不可逆转 脊髓损伤致截瘫或截瘫是单项最多的 胸腹主动脉手术的毁灭性并发症。 手术系列记录了15到38岁的永久性脊髓功能障碍 高危患者的百分比。我们已经合成并开始评估一种药物 候选，ATL146e，实质上抑制兔脊髓损伤。 我们在初步研究中证实，这种模式是可以重现的，而且 ATL146e是重组人A2a的有效选择性激动剂 腺苷受体。第一阶段提案的目标1旨在进一步 描述生产所需的ATL1 46e的时间窗口和剂量 最佳的脊髓保护。AIM 2旨在开发一种新的合成材料 该方案将允许放大合成ATL146e。稳定性研究 将启动以评估活性成分的保质期和 配方。这些研究将有助于ATL146e作为一种 药物，并将为第二阶段SBIR中描述的实验做准备 求婚。 建议的商业应用： 瘫痪是主动脉重建的一种毁灭性的并发症。在猪和兔的胸主动脉手术模型中，在脊髓再灌注期间全身应用腺苷类似物ATL-146E可以保护神经元的存活和脊髓的功能。这项研究的商业应用是将ATL-146E或更理想的化合物开发成治疗药物，用于胸主动脉手术期间的给药。这种药物的开发将解决未得到满足的医疗需求。

DESCRIPTION (provided by applicant): The central goal of this research is to develop a new drug to prevent spinal cord reperfusion injury secondary to aortic clamping that occurs frequently during thoracic surgery. Irreversible spinal cord injury resulting in paraplegia or paraparesis is the single most devastating complication of surgery on the thoracic and thoracoabdominal aorta. Surgical series have documented permanent spinal cord dysfunction in 15 to 38 percent of high-risk patients. We have synthesized and begun to evaluate a drug candidate, ATL146e that substantially inhibits spinal cord injury in rabbits. We have established in preliminary studies that this model is reproducible and that ATL146e is a potent and selective agonist of recombinant human A2A adenosine receptors. Aim 1 of the phase 1 proposal is designed to further characterize the time window and dose of ATL1 46e that is required to produce optimal spinal cord protection. Aim 2 is designed to develop a new synthetic scheme that will permit scale up the synthesis of ATL146e. Stability studies will be initiated to evaluate the shelf life of the active ingredient and formulations. These studies will facilitate the development of ATL146e as a drug and will prepare us for the experiments described in the phase II SBIR proposal. PROPOSED COMMERCIAL APPLICATION: Paralysis is a devastating complication of aortic reconstruction. In porcine and rabbit models of thoracic aortic surgery, systemic administration of an adenosine analogue, ATL-146e, during spinal cord reperfusion preserved neuronal viability and spinal cord function. The commerical applications of this research are development of ATL-146e or more optimal compounds into therapeutic drugs for administration during thoracic aortic surgeries. Development of such a drug would address an unmet medical need.