NOVEL ADENOSINE A2A AGONISTS IN RENAL TISSUE PROTECTION

DESCRIPTION (provided by applicant): The development of new treatments for the effective reduction of renal injury associated with acute renal failure and kidney transplantation will have a great impact on health care delivery to patients with renal disease. Acute ischemic renal failure affects 5 percent of hospitalized patients and has a mortality rate approaching 50 percent. At present, dialysis is the only FDA-approved treatment for acute renal failure. lschemia-reperfusion injury at the time of kidney transplantation causes delayed graft function and shortens graft survival. The long-term goal of this project is to evaluate the ability of a proprietary A2A adenosine receptor (A2A-AR) agonist, ATL146e to reduce renal injury in humans. The current proposal aims at completing the preclinical characterization of ATL 146e, a potent and selective A2A-AR agonist that has optimum pharmacological characteristics. Aim I addresses FDA requirements for toxicology, pharmacokinetics and metabolism. Aim 2 devises more efficient synthetic methods so that scale-up can support expanded preclinical studies and guide synthesis by certified Good Manufacturing Practices to support human studies. Aim 3 develops an in vivo assay for ATL 146e-mediated anti-inflammatory activity. Aim 4 tests the efficacy of ATL 146e in reducing injury in model of acute ischemia-reperfusion associated with kidney transplantation. PROPOSED COMMERCIAL APPLICATION: The incidence of azotemia, which includes all cases of acute renal failure (volume depletion, obstruction and intrinsic causes such as ischemia and toxins), was estimated in 1997 to be 275,000 patients per year. Additionally, it is estimated that all cases of azotemia are increasing at rate of 16,000 patients/year. The goal of this research is to develop a pharmaceutical product which will address this unmet medical need. All of the specific aims in this project are required by the FDA and ICH for drug development.