Optimization of 2-Amino-4,6-diarylpyrimidine-5-carbonitriles as Potent and Selective A(1) Antagonists

[Image: see text] We herein document a large collection of 108 2-amino-4,6-disubstituted-pyrimidine derivatives as potent, structurally simple, and highly selective A(1)AR ligands. The most attractive ligands were confirmed as antagonists of the canonical cyclic adenosine monophosphate pathway, and some pharmacokinetic parameters were preliminarilly evaluated. The library, built through a reliable and efficient three-component reaction, comprehensively explored the chemical space allowing the identification of the most prominent features of the structure–activity and structure–selectivity relationships around this scaffold. These included the influence on the selectivity profile of the aromatic residues at positions R(4) and R(6) of the pyrimidine core but most importantly the prominent role to the unprecedented A(1)AR selectivity profile exerted by the methyl group introduced at the exocyclic amino group. The structure–activity relationship trends on both A(1) and A(2A)ARs were conveniently interpreted with rigorous free energy perturbation simulations, which started from the receptor-driven docking model that guided the design of these series.