2-Amino-N-pyrimidin-4-ylacetamides as A2A receptor antagonists: 2. Reduction of hERG activity, observed species selectivity, and structure-activity relationships

J Med Chem. 2008 Mar 27;51(6):1730-9. doi: 10.1021/jm701187w. Epub 2008 Feb 29.


Previously we have described a series of novel A 2A receptor antagonists with excellent water solubility. As described in the accompanying paper, the antagonists were first optimized to remove an unsubstituted furyl moiety, with the aim of avoiding the potential metabolic liabilities that can arise from the presence of an unsubstituted furan. This effort identified a series of potent and selective methylfuryl derivatives. Herein, we describe the further optimization of this series to increase potency, maintain selectivity for the human A 2A vs the human A 1 receptor, and minimize activity against the hERG channel. In addition, the observed structure-activity relationships against both the human and the rat A 2A receptor are reported.

MeSH terms

  • Acetamides / chemical synthesis
  • Acetamides / chemistry
  • Acetamides / pharmacology*
  • Adenosine A1 Receptor Antagonists
  • Adenosine A2 Receptor Antagonists*
  • Animals
  • Drug Evaluation, Preclinical
  • Ether-A-Go-Go Potassium Channels / antagonists & inhibitors*
  • Ether-A-Go-Go Potassium Channels / metabolism
  • Hepatocytes / drug effects
  • Humans
  • Male
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / metabolism
  • Molecular Structure
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Rats
  • Rats, Wistar
  • Species Specificity
  • Stereoisomerism
  • Structure-Activity Relationship


  • Acetamides
  • Adenosine A1 Receptor Antagonists
  • Adenosine A2 Receptor Antagonists
  • Ether-A-Go-Go Potassium Channels
  • Pyrimidines