Pyrimidine derivatives as potent and selective A3 adenosine receptor antagonists

J Med Chem. 2011 Jan 27;54(2):457-71. doi: 10.1021/jm100843z. Epub 2010 Dec 27.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine A3 Receptor Antagonists / chemical synthesis*
  • Adenosine A3 Receptor Antagonists / chemistry
  • Adenosine A3 Receptor Antagonists / pharmacology
  • Amides / chemical synthesis*
  • Amides / chemistry
  • Amides / pharmacology
  • Amino Acid Sequence
  • Animals
  • Cell Line
  • Cricetinae
  • Cricetulus
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology
  • Quantitative Structure-Activity Relationship
  • Radioligand Assay
  • Sequence Homology, Amino Acid


  • Adenosine A3 Receptor Antagonists
  • Amides
  • Pyrimidines