Long Acting Agonists of Adenosine A2a Receptors

腺苷 A2a 受体长效激动剂

• 批准号: 6643850
• 负责人: ROBERT D THOMPSON
• 金额: $ 10.09万
• 依托单位: ADENOSINE THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2004-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6643850
• 关键词: G protein; adenosine; bioassay; biological signal transduction; chemical synthesis; chronic obstructive pulmonary disease; inflammation; laboratory rat; mass spectrometry; neurotransmitter agonist; neurotransmitter receptor; nuclear magnetic resonance spectroscopy; pharmacokinetics; purinergic receptor; receptor coupling; stereochemistry; technology /technique development

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.

描述（申请人提供）：腺苷是一种内源性核苷，通过四个G蛋白偶联受体A1、A2A、A2B和A3发挥其生理作用。 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 正在开发用于冠状动脉成像，并且已被证明对多种炎症动物模型有效。 由于其半衰期短，它不是治疗慢性阻塞性肺病（COPD）等慢性炎症性疾病的理想候选药物，使用长效化合物治疗效果更好。 最近，我们发现了一类新型化合物，其比 ATL-146e 具有更强的效力和作用持续时间，但选择性较低。 因此，该提案的目标是合成有效且具有选择性的长效 A2A 激动剂。 我们将在功能性生物测定中评估这些化合物，该生物测定已被证明是预测化合物作用持续时间的有用且有效的工具。 由于口服给药可能是优选的给药途径，因此第二个目标是鉴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 协议评估最佳候选者的标准 PK 参数。