A2a Adenosine Agonists as Neuroprotectants

A2a 腺苷激动剂作为神经保护剂

• 批准号: 6444325
• 负责人: ROBERT D THOMPSON
• 金额: $ 13.73万
• 依托单位: ADENOSINE THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-15 至 2002-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6444325
• 关键词: adenosine; antiinflammatory agents; biotechnology; biotherapeutic agent; disease /disorder prevention /control; dosage forms; drug design /synthesis /production; laboratory rabbit; neuroanatomy; neuropharmacologic agent; neuropharmacology; neurophysiology; neuroprotectants; purinergic receptor; reperfusion; slow release drug; spinal cord injury; swine; thoracic surgery

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.

描述（由申请人提供）：这项研究的核心目标是 开发一种新药，以防止继发于脊髓再灌注损伤 胸手术期间经常发生主动脉夹具。不可逆转 脊髓损伤导致截瘫或瘫痪是最单一的 胸腔和胸动主动脉的毁灭性手术并发症。 手术系列记录了15至38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药物 候选人ATL146E基本上抑制了兔子的脊髓损伤。 我们已经在初步研究中确定了该模型可再现，并且 ATL146E是重组人A2a的有效和选择性激动剂 腺苷受体。第1阶段提案的目标1旨在进一步 表征产生ATL1 46E的时间窗口和剂量 最佳的脊髓保护。 AIM 2旨在开发新的合成 将允许扩大ATL146E的合成的方案。稳定研究 将开始评估活性成分的保质期和 配方。这些研究将促进ATL146E作为一个 药物，将为我们做好准备，以准备II期SBIR中描述的实验 提议。 拟议的商业应用： 瘫痪是主动脉重建的毁灭性并发症。在脊髓再灌注过程中，腺苷类似物ATL-146E的猪和兔模型在脊髓再灌注过程中的全身性给药保留了神经元的生存力和脊髓功能。这项研究的商业应用是在胸主动脉手术期间对治疗药物进行ATL-146E或更佳化合物的开发。这种药物的开发将满足未满足的医疗需求。