Potent, selective, and orally active adenosine A2A receptor antagonists: arylpiperazine derivatives of pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines

Bioorg Med Chem Lett. 2007 Mar 1;17(5):1376-80. doi: 10.1016/j.bmcl.2006.11.083. Epub 2006 Dec 3.

Abstract

Antagonism of the adenosine A2A receptor offers great promise in the treatment of Parkinson's disease. Employing the known pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine A2A antagonist SCH 58261 as a starting point, we identified the potent and selective (vs. A1) antagonist 11h, orally active in the rat haloperidol-induced catalepsy model. We further optimized this lead to the methoxyethoxyethyl ether 12a (SCH 420814), which shows broad selectivity, good pharmacokinetic properties, and excellent in vivo activity.

MeSH terms

  • Adenosine A2 Receptor Antagonists*
  • Administration, Oral
  • Animals
  • Catalepsy / chemically induced
  • Catalepsy / drug therapy
  • Disease Models, Animal
  • Parkinson Disease / drug therapy
  • Piperazine
  • Piperazines / administration & dosage
  • Piperazines / chemical synthesis*
  • Piperazines / pharmacokinetics
  • Pyrimidines / administration & dosage
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / pharmacokinetics
  • Rats
  • Structure-Activity Relationship
  • Substrate Specificity
  • Treatment Outcome

Substances

  • Adenosine A2 Receptor Antagonists
  • Piperazines
  • Pyrimidines
  • Piperazine