Structure-activity studies of 5-substituted pyridopyrimidines as adenosine kinase inhibitors

Bioorg Med Chem Lett. 2001 Jan 8;11(1):83-6. doi: 10.1016/s0960-894x(00)00602-8.


The synthesis and SAR of a novel series of non-nucleoside pyridopyrimidine inhibitors of the enzyme adenosine kinase (AK) are described. It was found that pyridopyrimidines with a broad range of medium and large non-polar substituents at the 5-position potently inhibited AK activity. A narrower range of analogues was capable of potently inhibiting adenosine phosphorylation in intact cells indicating an enhanced ability of these analogues to penetrate cell membranes. Potent AK inhibitors were found to effectively reduce nociception in animal models of thermal hyperalgesia and persistent pain.

MeSH terms

  • Adenosine Kinase / antagonists & inhibitors*
  • Adenosine Kinase / metabolism
  • Administration, Oral
  • Animals
  • Cell Membrane Permeability
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use
  • Hyperalgesia / drug therapy
  • Inhibitory Concentration 50
  • Molecular Structure
  • Pain / drug therapy
  • Pain Measurement / drug effects
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacology*
  • Pyrimidines / therapeutic use
  • Rats
  • Structure-Activity Relationship


  • Enzyme Inhibitors
  • Pyrimidines
  • Adenosine Kinase