A2a Adenosine Agonists Limit Damage from Infection

描述(申请人提供)：败血症综合征是第11位主要原因 美国的死亡人数(每年约90万新病例)与 死亡率约为35%。对辅助治疗的需求是迫切的。在……里面 在这项SBIR奖的第一阶段，我们记录了 腺苷A2a受体(A2AAR)激动剂作用于分离的免疫细胞 观察到脂多糖组小鼠存活率显著提高 活体大肠杆菌引起的感染性休克。新合成的30个A2AAR的筛选 激动剂表明，原型ATL146e仍然是最有效的， 有选择性，最不可能有有毒的代谢物。在第二阶段，我们建议 针对IND应用的ATL146e的其他研究。目标1将 描述急性、单次给药的毒理学、药代动力学和代谢 ATL146e。目标2将开发放大合成的方法 2-碘-NECA，合成ATL146e的关键中间体，将 对其稳定性、溶解性和制剂进行表征。目标3将进行优化 ATL146e对小鼠大肠杆菌腹膜炎模型的治疗方案 菌血症。目的4检查ATL146e治疗对终点的影响 除死亡外，即肝、肾、肺功能障碍以及 对细胞因子的反应，这可能对患者监测有用。 拟议的商业应用：只有一种产品，活性蛋白C，预计将进入市场，并具有治疗脓毒症的适应症。然而，临床研究表明，每接受16次治疗，只有一人获救。迫切需要更多的治疗选择，以满足这一未得到满足的医疗需求。一种包含A2A激动剂作为活性成分的药物产品将是医生在对抗败血症方面非常有价值的补充，这也是本研究的目标。

DESCRIPTION (Provided by applicant): Sepsis 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 dramatically 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. PROPOSED COMMERCIAL APPLICATION: Only one product, Activated Protein C, is expected to reach the market with an indication to treat sepsis. Clinical studies, however, have demonstrated that only one life was saved for every 16 treated. Additional options for treatment are urgently required to address this unmet medical need. A pharmaceutical product that contains an A2A agonist as the active ingredient would be a very valuable addition to the physician's armament in fighting sepsis and is the goal of this research.