Pyrimidine Derivatives as Potent and Selective A3 Adenosine Receptor Antagonists

摘要: Two regioisomeric series of diaryl 2- or 4-amidopyrimidines have been synthesized and their adenosine receptor affinities were determined in radioligand binding assays at the four human receptors (hARs). Some ligands prepared herein exhibit remarkable (K(i) < 10 nm) and, most noticeably, absence activity A(1), A(2A), A(2B) receptors. The structural determinants that support affinity selectivity profiles highlighted through an integrated computational approach, combining a 3D-QSAR model built on second generation GRid INdependent Descriptors (GRIND2) with novel homology hA(3) receptor. robustness was subsequently evaluated by design new derivatives exploring alkyl substituent exocyclic amide group. synthesis evaluation compounds validated predictive power model, exhibiting excellent agreement between predicted experimental activities.