A2A ADENOSINE AGONISTS LIMIT DAMAGE FROM INFECTION

epsis syndrome is the 11th leading cause of death in the United States ( about 900,000 new cases per year) with a mortality of about 35 percent. The need for adjunctive therapies is urgent. In Phase I of this SBIR award we documented the anti-inflammatory effects of adenosine A2A receptor (A2AAR) agonists on isolated immune cells and have observed ramatically improved survival in mouse models of Iipopolysaccaride-and live E. coli-induced septic shock. Screening 30 newly-synthesized A2AAR agonists showed that the prototype, ATL146e, remained the most potent, selective and least likely to have toxic metabolites. In phase II we propose additional studies on ATL146e aiming at an IND application. Aim 1 will characterize the acute, single-dose toxicology, pharmacokinetics and metabolism of ATL146e. Aim 2 will develop methods for the scale-up of the synthesis of 2-iodoNECA, the key intermediate in the synthesis of ATL146e, and will characterize its stability, solubility and formulation. Aim 3 will optimize treatment regimens with ATL146e in a mouse model of E. coli peritonitis and bacteremia. Aim 4 examines the effect of treatment with ATL146e on end points other than mortality, namely dysfunction of liver, kidney and lung, as well as on cytokine responses that could be useful in patient monitoring.