A2a Adenosine Agonists for Diabetic Nephropathy

描述（由申请人提供）：糖尿病肾病（DN）约占需要透析或移植的肾衰竭病例的40%。此外，糖尿病肾病与明显更高的发病率和死亡率相关。重要的是开发新的干预措施来预防糖尿病并发症。炎症在糖尿病及其并发症的发生中被认为是重要的致病机制。腺苷2A受体（A2AR）在肾脏以及骨髓来源的细胞中表达，并且我们先前已经表明，当急性施用时，A2AR在活化后减少炎症。我们的初步数据表明，A2A R激动剂具有深远的影响，以减少肾损伤时，长期输注在大鼠模型的链脲佐菌素（STZ）诱导的糖尿病肾病。腺苷治疗有限责任公司最近开发了ATL 313，一种新的口服活性A2A R激动剂。本I期申请的第一个目的是检查ATL 313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ATL 313在糖尿病肾病的一级和二级预防中有效的原理证据。ATL 313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进一步测试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.