Discovery of Potent and Selective A2A Antagonists with Efficacy in Animal Models of Parkinson’s Disease and Depression

Adenosine A2A receptor(A2AAdoR) antagonismis a nondopaminergic approach to Parkinson’s diseasetreatment that is under development. Earlier we had reported the therapeutic potential of 7-methoxy-4- morpholino- benzothiazolederivatives as A2AAdoR antagonists. We herein described a novel series of [1,2,4]triazolo[5,1-f]purin-2-one derivatives that displays functional antagonismof the A2A receptor with a high degree of selectivity over A1, A2B, and A3 receptors. Compounds from this new scaffold resulted in the discovery of highly potent, selective, stable, and moderate brain penetrating compound 33. Compound 33 endowed with satisfactory in vitro and in vivo pharmacokinetics properties. Compound 33 demonstrated robust oral efficacies in two commonly used models of Parkinson’s disease( haloperidol-induced catalepsyand 6-OHDA lesioned rat models) and depression (TST and FST mice models).