Novel Adenosine A2A Agonists in Renal Tissue Protection

描述(由申请者提供)：新的治疗方法的发展 有效减少与急性肾功能衰竭相关的肾损伤和 肾移植将对卫生保健服务的提供产生重大影响 患有肾脏疾病的患者。急性缺血性肾功能衰竭影响5% 患者住院，死亡率接近50%。在… 目前，透析是FDA批准的唯一治疗急性肾功能衰竭的方法。 肾移植时的缺血再灌注损伤 移植物功能延迟，移植物存活时间缩短。这样做的长期目标是 该项目是评估一种专有的A2A腺苷受体的能力 (A2A-AR)激动剂ATL146e，用于减少人类的肾脏损伤。海流 提案旨在完成ATL 146e的临床前表征， 具有最佳药理作用的有效和选择性A2A-AR激动剂 特点。AIM I涉及FDA对毒理学的要求， 药物动力学和代谢。目标2设计出更有效的合成方法 以便扩大规模可以支持扩大临床前研究和指导合成 通过认证的良好制造规范来支持人体研究。目标3 建立ATL 146E介导的抗炎活性的体内检测方法。目标 4检测ATL146E对急性脑损伤模型的保护作用 肾移植相关的缺血再灌流。 拟议的商业应用：氮质血症的发病率，包括所有急性肾功能衰竭(容量耗尽、梗阻和诸如缺血和毒素等内在原因)的病例，1997年估计为每年275,000名患者。此外，据估计，所有氮质血症病例正在以每年16000名患者的速度增加。这项研究的目标是开发一种药物产品，以满足这一未得到满足的医疗需求。该项目中的所有具体目标都是FDA和ICH在药物开发方面所要求的。

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.