title: Pyrimidine derivatives as potent and selective A3 adenosine receptor antagonists.
abstract: 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 adenosine receptors (hARs). Some of the ligands prepared herein exhibit remarkable affinities (K(i) < 10 nm) and, most noticeably, the absence of activity at the A(1), A(2A), and A(2B) receptors. The structural determinants that support the affinity and selectivity profiles of the series were highlighted through an integrated computational approach, combining a 3D-QSAR model built on the second generation of GRid INdependent Descriptors (GRIND2) with a novel homology model of the hA(3) receptor. The robustness of the computational model was subsequently evaluated by the design of new derivatives exploring the alkyl substituent of the exocyclic amide group. The synthesis and evaluation of the novel compounds validated the predictive power of the model, exhibiting excellent agreement between predicted and experimental activities.
authors.affiliation: Combinatorial Chemistry Unit (COMBIOMED), Institute of Industrial Pharmacy, University of Santiago de Compostela, Santiago de Compostela, 15782, Spain.
authors.forename: Vicente
authors.initials: V
authors.lastname: Yaziji
authors.forename: David
authors.initials: D
authors.lastname: Rodríguez
authors.forename: Hugo
authors.initials: H
authors.lastname: Gutiérrez-de-Terán
authors.forename: Alberto
authors.initials: A
authors.lastname: Coelho
authors.forename: Olga
authors.initials: O
authors.lastname: Caamaño
authors.forename: Xerardo
authors.initials: X
authors.lastname: García-Mera
authors.forename: José
authors.initials: J
authors.lastname: Brea
authors.forename: María Isabel
authors.initials: MI
authors.lastname: Loza
authors.forename: María Isabel
authors.initials: MI
authors.lastname: Cadavid
authors.forename: Eddy
authors.initials: E
authors.lastname: Sotelo
mesh_terms: D058918:Adenosine A3 Receptor Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D011869:Radioligand Assay; D017386:Sequence Homology, Amino Acid
chemical_list: D058918:Adenosine A3 Receptor Antagonists; D000577:Amides; D011743:Pyrimidines