Antagonists of the human A(2A) adenosine receptor. 4. Design, synthesis, and preclinical evaluation of 7-aryltriazolo[4,5-d]pyrimidines

Roger J Gillespie, Samantha J Bamford, Ruth Botting, Mike Comer, Sarah Denny, Suneel Gaur, Michael Griffin, Allan M Jordan, Anthony R Knight, Joanne Lerpiniere, Stefania Leonardi, Sean Lightowler, Steven McAteer, Angela Merrett, Anil Misra, Antony Padfield, Mark Reece, Mona Saadi, Daniel L Selwood, Gemma C StrattonDominic Surry, Richard Todd, Xin Tong, Vicki Ruston, Rebecca Upton, Scott M Weiss

Research output: Contribution to journalArticlepeer-review


Antagonism of the human A(2A) receptor has been implicated as a point of therapeutic intervention in the alleviation of the symptoms associated with Parkinson's disease. This is thought to occur, at least in part, by increasing the sensitivity of the dopaminergic neurons to the residual, depleted levels of striatal dopamine. We herein describe a novel series of functionalized triazolo[4,5-d]pyrimidine derivatives that display functional antagonism of the A(2A) receptor. Optimization of these compounds has resulted in improvements in potency, selectivity, and the pharmacokinetic properties of key derivatives. These efforts have led to the discovery of 60 (V2006/BIIB014), which demonstrates strong oral activity in commonly used models of Parkinson's disease. Furthermore, this derivative has shown excellent preclinical pharmacokinetics and has successfully completed phase I clinical studies. This compound is presently undergoing further clinical evaluation in collaboration with Biogen Idec.

Original languageEnglish
Pages (from-to)33-47
Number of pages15
JournalJournal of Medicinal Chemistry
Issue number1
Publication statusPublished - 8 Jan 2009


  • Adenosine A2 Receptor Antagonists
  • Amines
  • Animals
  • Azoles
  • Drug Design
  • Drug Evaluation, Preclinical
  • Gait Disorders, Neurologic
  • Haloperidol
  • Humans
  • Mice
  • Molecular Structure
  • Pyrimidines
  • Rats
  • Receptor, Adenosine A2A
  • Structure-Activity Relationship

Research Beacons, Institutes and Platforms

  • Photon Science Institute
  • Manchester Cancer Research Centre


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