Long Acting Agonists of Adenosine A2a Receptors

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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.