A2a Adenosine Agonists for Diabetic Nephropathy

描述(申请人提供)：糖尿病肾病约占需要透析或移植的肾功能衰竭病例的40%。此外，糖尿病肾病与明显较高的发病率和死亡率有关。开发新的干预措施来预防糖尿病并发症是很重要的。炎症在糖尿病及其并发症的发生中被认为是一个重要的致病机制。腺苷2A受体(A2ARs)在肾脏和骨髓来源的细胞中都有表达，我们之前已经证明，A2ARs在激活后可以在急性给药时减轻炎症。我们的初步数据表明，在链脲佐菌素(STZ)诱导的糖尿病肾病大鼠模型中，A2AR激动剂有显著的减轻肾脏损伤的作用。腺苷治疗公司最近开发了ATL313，一种新型的口服活性A2AR激动剂。这一第一阶段应用的第一个目标是检查ATL313的药代动力学、口服生物利用度和初步毒理学。第二个目的是证明ATL313在糖尿病肾病的一级和二级预防中是有效的原则证明。ATL313将通过渗透性微型泵给药，以确定其疗效。这将使我们为第二阶段的目标做好准备，即通过口服进一步测试该化合物。

DESCRIPTION (provided by applicant): Diabetic nephropathy (DN) accounts for approximately 40% of the cases of renal failure requiring dialysis or transplantation. Moreover, diabetic nephropathy is associated with markedly higher morbidity and mortality rates. It is important to develop novel interventions to prevent complications of diabetes. Inflammation in the genesis of diabetes, as well as its complications, is considered an important pathogenic mechanism. Adenosine 2A receptors (A2ARs) are expressed in kidney as well as bone marrow derived cells and we have previously shown that upon activation A2A Rs reduces inflammation when administered acutely. Our preliminary data demonstrate that A2A R agonists have profound effects to reduce renal injury when infused chronically in a rat model of streptozotocin (STZ)-induced diabetic nephropathy. Adenosine Therapeutics, LLC has recently developed ATL313, a novel, orally active A2A R agonist. The 1st Aim of this Phase 1 application is to examine the pharmacokinetics, oral bioavailability and initial toxicology of ATL313. The 2nd Aim is to demonstrate the proof of principle that ATL313 is effective in primary and secondary prevention of diabetic nephropathy. ATL313 will be administered via osmotic mini-pumps to establish its efficacy. This will prepare us for the Phase 2 goal of further testing of the compound through oral administration.