A2a Adenosine Agonists as Neuroprotectants

描述（由申请人提供）：本研究的中心目标是 开发一种新的药物，以防止脊髓再灌注损伤继发于 胸外科手术中经常发生的主动脉夹闭。不可逆 脊髓损伤导致截瘫或轻瘫是最常见的 胸部和胸腹主动脉手术的毁灭性并发症。 手术系列记录了15至38年的永久性脊髓功能障碍 高风险患者的百分比。我们已经合成并开始评估一种药物 候选物，ATL 146 e，其实质上抑制兔中的脊髓损伤。 我们在初步研究中已经确定，该模型是可重复的， ATL 146 e是重组人A2 A有效和选择性激动剂 腺苷受体。第一阶段提案的目标1旨在进一步 表征产生所需的ATL 1 46 e的时间窗和剂量 最佳的脊髓保护Aim 2旨在开发一种新的合成 该方案将允许放大ATL 146 e的合成。稳定性研究 将开始评价活性成分的有效期， 制剂。这些研究将促进ATL 146 e作为一种 药物，并将准备我们在第二阶段SBIR中描述的实验 提议 拟定商业应用： 瘫痪是主动脉重建术的致命并发症。在猪和兔胸主动脉手术模型中，在脊髓再灌注期间全身给予腺苷类似物ATL-146 e可保护神经元活力和脊髓功能。本研究的临床应用是将ATL-146 e或更优化的化合物开发成用于胸主动脉手术期间给药的治疗药物。开发这种药物将解决未满足的医疗需求。

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.