title: Selective and potent adenosine A3 receptor antagonists by methoxyaryl substitution on the N-(2,6-diarylpyrimidin-4-yl)acetamide scaffold.
abstract: The influence of diverse methoxyphenyl substitution patterns on the N-(2,6-diarylpyrimidin-4-yl)acetamide scaffold is herein explored in order to modulate the A(3) adenosine receptor antagonistic profile. As a result, novel ligands exhibiting excellent potency (K(i) on A(3) AR < 20 nM) and selectivity profiles (above 100-fold within the adenosine receptors family) are reported. Moreover, our joint theoretical and experimental approach allows the identification of novel pharmacophoric elements conferring A(3)AR selectivity, first established by a robust computational model and thereafter characterizing the most salient features of the structure-activity and structure-selectivity relationships in this series.
authors.affiliation: Combinatorial Chemistry Unit (COMBIOMED), Center for Research in Biological Chemistry and Molecular Materials (CIQUS), University of 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: Alberto
authors.initials: A
authors.lastname: Coelho
authors.forename: Xerardo
authors.initials: X
authors.lastname: García-Mera
authors.forename: Abdelaziz
authors.initials: A
authors.lastname: El Maatougui
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: Hugo
authors.initials: H
authors.lastname: Gutiérrez-de-Terán
authors.forename: Eddy
authors.initials: E
authors.lastname: Sotelo
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis* / Q000737:chemistry; D058918:Adenosine A3 Receptor Antagonists / Q000737:chemistry*; D000840:Anisoles / Q000138:chemical synthesis* / Q000737:chemistry; D001665:Binding Sites; D003198:Computer Simulation; D006801:Humans; D008958:Models, Molecular; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000081:Acetamides; D058918:Adenosine A3 Receptor Antagonists; D000840:Anisoles; D011743:Pyrimidines; C030686:acetamide; C060998:anisole