A2a Adenosine Agonists Limit Damage from Infection

A2a 腺苷激动剂可限制感染造成的损害

• 批准号: 6483754
• 负责人: ROBERT D THOMPSON
• 金额: $ 51.61万
• 依托单位: ADENOSINE THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2004-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6483754
• 关键词: Escherichia coli; adenosine; antibiotics; antiinfective agents; antiinflammatory agents; bacterial disease; blood toxicology; drug design /synthesis /production; inflammation; laboratory mouse; peritonitis; pharmacokinetics; purinergic receptor; receptor binding; stimulant /agonist

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.

描述（申请人提供）：败血症综合征是第11个主要原因 美国死亡（每年约900,000例新案件） 死亡率约为35％。紧急辅助疗法的需求是紧急的。在 该SBIR奖的第一阶段我们记录了 腺苷A2A受体（A2AAR）激动剂在分离的免疫细胞上，并具有 观察到的iipopolysaccaride小鼠模型的生存率显着提高，并且 活的大肠杆菌引起的败血性休克。筛选30个新合成的A2AAR 激动剂表明，原型ATL146E仍然是最有效的， 选择性，最不可能具有有毒代谢物。在第二阶段，我们提出了 针对IND应用的ATL146E的其他研究。目标1意志 表征急性，单剂量毒理学，药代动力学和代谢 Atl146e的AIM 2将开发用于扩大合成的方法 2-iodoneca，ATL146E合成中的关键中间体，将 表征其稳定性，溶解度和配方。 AIM 3将优化 在大肠杆菌腹膜炎的小鼠模型和 菌血症。 AIM 4检查用ATL146E治疗对终点的影响 除了死亡率，即肝，肾脏和肺的功能障碍，以及 关于可用于患者监测的细胞因子反应。 拟议的商业应用：只有一种激活蛋白C的产品有望进入市场，以表明治疗败血症。然而，临床研究表明，每16种治疗只能挽救一种生命。 迫切需要其他治疗的其他选择来满足这种未满足的医疗需求。包含A2A激动剂的药品作为活性成分将是对败血症作斗争的医生军备的非常有价值的补充，并且是这项研究的目标。