Discovery of 7‑(Prolinol‑<i>N</i>‑yl)-2-phenylamino-thiazolo[5,4‑<i>d</i>]pyrimidines as Novel Non-Nucleoside Partial Agonists for the A_2A Adenosine Receptor: Prediction from Molecular Modeling

Abstract

We describe the identification of 7-(prolinol-<i>N</i>-yl)-2-phenylamino-thiazolo­[5,4-<i>d</i>]­pyrimidines as a novel chemotype of non-nucleoside partial agonists for the A_2A adenosine receptor (A_2AAR). Molecular-modeling indicated that the (<i>S</i>)-2-hydroxymethylene-pyrrolidine could mimic the interactions of agonists’ ribose, suggesting that this class of compounds could have agonistic properties. This was confirmed by functional assays on the A_2AAR, where their efficacy could be associated with the presence of the 2-hydroxymethylene moiety. Additionally, the best compound displays promising affinity, selectivity profile, and physicochemical properties