Potent and orally bioavailable 8-bicyclo[2.2.2]octylxanthines as adenosine A1 receptor antagonists

J Med Chem. 2006 Nov 30;49(24):7119-31. doi: 10.1021/jm0605381.


In the search for a selective adenosine A1 receptor antagonist with greater aqueous solubility than the compounds currently in clinical trials as diuretics, a series of 1,4-substituted 8-cyclohexyl and 8-bicyclo[2.2.2]octylxanthines were investigated. The binding affinities of a variety of cyclohexyl and bicyclo[2.2.2]octylxanthines for the rat and human adenosine A1, A2A, A2B, and A3 receptors are presented. Bicyclo[2.2.2]octylxanthine 16 exhibited good pharmaceutical properties and in vivo activity in a rat diuresis model (ED50=0.3 mg/kg po). Optimization of the bridgehead substituent led to propionic acid 29 (BG9928), which retained high potency (hA1, Ki=7 nM) and selectivity for the adenosine A1 receptor (915-fold versus adenosine A2A receptor; 12-fold versus adenosine A2B receptor) with improved oral efficacy in the rat diuresis model (ED50=0.01 mg/kg) as well as high oral bioavailability in rat, dog, and cynomolgus monkey.

MeSH terms

  • Adenosine A1 Receptor Antagonists*
  • Administration, Oral
  • Animals
  • Biological Availability
  • Brain / metabolism
  • Cell Line
  • Cricetinae
  • Cricetulus
  • Diuresis / drug effects
  • Dogs
  • Heart Atria / drug effects
  • Humans
  • In Vitro Techniques
  • Macaca fascicularis
  • Male
  • Radioligand Assay
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship
  • Xanthines / chemical synthesis*
  • Xanthines / pharmacokinetics
  • Xanthines / pharmacology


  • Adenosine A1 Receptor Antagonists
  • BG 9928
  • Xanthines