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（由申请人提供）：脓毒症综合征是第11位主要原因 美国的死亡率（每年约90万例新病例） 死亡率约为35%。因此，迫切需要进行预防性治疗。在 在SBIR奖项的第一阶段，我们记录了 腺苷A2 A受体（A2 AAR）激动剂对分离的免疫细胞的作用，并且具有 在脂多糖小鼠模型中观察到显著改善的存活率， 活的大肠大肠杆菌引起的感染性休克筛选30个新合成的A2 AAR 激动剂显示，原型ATL 146 e仍然是最有效的， 选择性和最不可能有毒性代谢物。在第二阶段，我们建议 针对IND申请的ATL 146 e的其他研究。目标1将 表征急性、单次给药毒理学、药代动力学和代谢 ATL 146 e的Aim 2将开发用于放大合成 2-iodoNECA是合成ATL 146 e的关键中间体， 表征其稳定性、溶解性和制剂。目标3将优化 在E.大肠杆菌性腹膜炎， 菌血症目的4检查用ATL 146 e治疗对终点的影响 除了死亡，即肝、肾和肺功能障碍，以及 对细胞因子反应的研究，这可能对病人的监测很有用。 拟议的商业应用：只有一种产品，活化蛋白C，预计将进入市场，适应症治疗败血症。然而，临床研究表明，每16名接受治疗的人中只有一人获救。 迫切需要更多的治疗选择，以解决这一未满足的医疗需求。含有A2 A激动剂作为活性成分的药物产品将是医生对抗败血症的非常有价值的补充，也是本研究的目标。