2-Amino-6-furan-2-yl-4-substituted nicotinonitriles as A2A adenosine receptor antagonists

J Med Chem. 2008 Aug 14;51(15):4449-55. doi: 10.1021/jm701594y. Epub 2008 Jul 19.


A 2A adenosine receptor antagonists usually have bi- or tricyclic N aromatic systems with varying substitution patterns to achieve desired receptor affinity and selectivity. Using a pharmacophore model designed by overlap of nonxanthine type of previously known A 2A antagonists, we synthesized a new class of compounds having a 2-amino nicotinonitrile core moiety. From our data, we conclude that the presence of at least one furan group rather than phenyl is beneficial for high affinity on the A 2A adenosine receptor. Compounds 39 (LUF6050) and 44 (LUF6080) of the series had K i values of 1.4 and 1.0 nM, respectively, with reasonable selectivity toward the other adenosine receptor subtypes, A 1, A 2B, and A 3. The high affinity of 44 was corroborated in a cAMP second messenger assay, yielding subnanomolar potency for this compound.

MeSH terms

  • Adenosine A2 Receptor Antagonists*
  • Amines / chemistry*
  • Animals
  • Cell Line
  • Cricetinae
  • Cyclic AMP / biosynthesis
  • Furans / chemistry*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Nicotinic Acids / chemistry*
  • Nicotinic Acids / classification
  • Nicotinic Acids / pharmacology*
  • Nitriles / chemistry*
  • Nitriles / classification
  • Nitriles / pharmacology*
  • Receptor, Adenosine A2A / metabolism
  • Structure-Activity Relationship


  • Adenosine A2 Receptor Antagonists
  • Amines
  • Furans
  • Nicotinic Acids
  • Nitriles
  • Receptor, Adenosine A2A
  • Cyclic AMP
  • furan