Trifluorinated Pyrimidine-Based A2B Antagonists: Optimization and Evidence of Stereospecific Recognition

J Med Chem. 2019 Oct 24;62(20):9315-9330. doi: 10.1021/acs.jmedchem.9b01340. Epub 2019 Oct 4.


We report the identification of two subsets of fluorinated nonxanthine A2B adenosine receptor antagonists. The novel derivatives explore the effect of fluorination at different positions of two pyrimidine-based scaffolds. The most interesting ligands combine excellent hA2B affinity (Ki < 15 nM) and remarkable subtype selectivity. The results of functional cAMP experiments confirmed the antagonistic behavior of representative ligands. The compounds were designed on the basis of previous molecular models of the stereoselective binding of the parent scaffolds to the hA2B receptor, and we herein provide refinement of such models with the fluorinated compounds, which allows the explanation of the spurious effects of the fluorination at the different positions explored. These models are importantly confirmed by a synergistic study combining chiral HPLC, circular dichroism, diastereoselective synthesis, molecular modeling, and X-ray crystallography, providing experimental evidence toward the stereospecific interaction between optimized trifluorinated stereoisomers and the hA2B receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine A2 Receptor Antagonists / chemistry*
  • Adenosine A2 Receptor Antagonists / metabolism
  • Binding Sites
  • Crystallography, X-Ray
  • Drug Design
  • Humans
  • Hydrogen Bonding
  • Ligands
  • Molecular Conformation
  • Molecular Dynamics Simulation
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Pyrimidines / chemistry*
  • Pyrimidines / metabolism
  • Receptor, Adenosine A2B / chemistry*
  • Receptor, Adenosine A2B / genetics
  • Receptor, Adenosine A2B / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship


  • Adenosine A2 Receptor Antagonists
  • Ligands
  • Protein Isoforms
  • Pyrimidines
  • Receptor, Adenosine A2B