A2A ADENOSINE AGONISTS AS NEUROPROTECTANTS

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.