A2a Adenosine Agonists for Diabetic Nephropathy

描述（由申请人提供）：糖尿病肾病（DN）约占肾衰竭需要透析或移植病例的40%。此外，糖尿病肾病与明显较高的发病率和死亡率相关。开发新的干预措施来预防糖尿病并发症是很重要的。炎症在糖尿病的发生及其并发症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表达，我们之前已经证明，在激活A2ARs后，急性给药可以减轻炎症。我们的初步数据表明，A2A R激动剂在长期输注链脲佐菌素（STZ）诱导的糖尿病肾病大鼠模型中具有显著的减轻肾损伤的作用。Adenosine Therapeutics， LLC最近开发了一种新型口服活性A2A R激动剂ATL313。该i期申请的第一个目的是检查ATL313的药代动力学、口服生物利用度和初始毒理学。第二个目的是证明ATL313在糖尿病肾病一级和二级预防中的有效性。ATL313将通过渗透微型泵给药以确定其疗效。这将为我们通过口服给药进一步测试该化合物的第二阶段目标做好准备。

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.