Scaffold decoration at positions 5 and 8 of 1,2,4-triazolo[1,5-c]pyrimidines to explore the antagonist profiling on adenosine receptors: a preliminary structure-activity relationship study

J Med Chem. 2014 Jul 24;57(14):6210-25. doi: 10.1021/jm500752h. Epub 2014 Jul 11.


The structure-activity relationship (SAR) of new 5,8-disubstituted-1,2,4-triazolo[1,5-c]pyrimidines as adenosine receptors (ARs) antagonists has been explored. All the synthesized compounds show affinity for the hA2A and hA3 ARs depending on the substitution patterns at the 5 and 8 positions. In particular, a free amino group at the 5 position with an ethoxycarbonyl group at the 8 position leads to potent and quite selective hA2A antagonists (compound 12: hA2A AR Ki=3.32 nM; hA1/hA2A=55.6; hA2A/hA3=0.01), whereas the introduction of a methylamino function at the 5 position yields a good binding profile at the hA3 AR (compound 23: hA3 AR Ki=4.14 nM, hA1/hA3=236; hA2A/hA3=25). Through an in silico receptor-driven approach, we have determined the most favorable orientation of the substitutions at the 5 and 8 positions of the 1,2,4-triazolo[1,5-c]pyrimidine (TP) scaffold and, accordingly, we have elucidated the observed SAR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dose-Response Relationship, Drug
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Purinergic P1 Receptor Antagonists / chemical synthesis
  • Purinergic P1 Receptor Antagonists / chemistry
  • Purinergic P1 Receptor Antagonists / pharmacology*
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Receptor, Adenosine A2A / chemistry
  • Receptor, Adenosine A2A / metabolism*
  • Receptor, Adenosine A3 / chemistry
  • Receptor, Adenosine A3 / metabolism*
  • Structure-Activity Relationship
  • Triazoles / chemical synthesis
  • Triazoles / chemistry
  • Triazoles / pharmacology*


  • 1,2,4-triazolo(1,5-c)pyrimidine
  • Purinergic P1 Receptor Antagonists
  • Pyrimidines
  • Receptor, Adenosine A2A
  • Receptor, Adenosine A3
  • Triazoles