Long Acting Agonists of Adenosine A2a Receptors

描述（申请人提供）：腺苷是一种内源性核苷，通过四种g蛋白偶联受体A1、A2A、A2B和A3发挥生理作用。Adenosine Therapeutics， LLC对A2A受体亚型介导的抗炎作用感兴趣。一种先导化合物ATL-146e正在开发中，用于冠状动脉成像，并已被证明在几种动物炎症模型中有效。由于半衰期短，它不是慢性炎症性疾病（如慢性阻塞性肺疾病（COPD））的理想候选者，使用长效化合物治疗效果更好。最近，我们发现了一类新的化合物，它比ATL-146e表现出更大的效力和持续的作用，但表现出更低的选择性。因此，本提案的目标是合成长效的强效和选择性的A2A激动剂。我们将在功能性生物测定法中评估这些化合物，该方法已被证明是预测化合物作用持续时间的有用和有效的工具。由于口服给药可能是一种较好的给药途径，第二个目标将是确定具有口服生物利用度的化合物。最后，我们将使用我们开发的标准LC/MS协议评估最佳候选物的标准PK参数。

DESCRIPTION (provided by applicant): Adenosine is an endogenous nucleoside that exerts its physiological effects through four G-protein coupled receptors A1, A2A, A2B, and A3. Adenosine Therapeutics, LLC is interested in the anti-inflammatory actions mediated by the A2A receptor subtype. A lead compound, ATL-146e, is being developed for coronary artery imaging and has also been shown to be efficacious in several animal models of inflammation. Due to its short half-life, it is not an ideal candidate for chronic inflammatory disorders such as chronic obstructive pulmonary disease (COPD), which would be better treated with a longer-acting compound. Recently, we discovered a novel class of compounds that shows greater potency and duration of action than ATL-146e, but exhibit decreased selectivity. Thus, the goal of this proposal is to synthesize long acting A2A agonists that are potent and selective. We will evaluate these compounds in a functional bioassay that has already been demonstrated to be a useful and efficient tool in predicting a compound's duration of action. As oral dosing may be a preferable route of administration, a secondary goal will be to identify compounds that have oral bioavailability. Finally, we will evaluate standard PK parameters for our best candidates using standard LC/MS protocols that we have developed.