Discovery of a novel A2B adenosine receptor antagonist as a clinical candidate for chronic inflammatory airway diseases

J Med Chem. 2008 Apr 10;51(7):2267-78. doi: 10.1021/jm7014815. Epub 2008 Mar 6.


Recently, we have reported a series of new 1,3-symmetrically (R 1 = R 3) substituted xanthines ( 3 and 4) which have high affinity and selectivity for the human adenosine A 2B receptors (hA(2B)-AdoR). Unfortunately, this class of compounds had poor pharmacokinetic properties. This prompted us to investigate the effect of differential alkyl substitution at the N-1 and N-3 positions ( N 1-R not equal to N 3-R) on A(2B)-AdoR affinity and selectivity; we had the dual objectives of enhancing affinity and selectivity for the A(2B)-AdoR, as well as improving oral bioavailability. This effort has led to the discovery of compound 62, that displayed high affinity and selectivity for the hA(2B)-AdoR (K(i) = 22 nM). In addition, compound 62 showed high functional potency in inhibiting the accumulation of cyclic adenosine monophosphate induced by 5'- N-ethylcarboxamidoadenosine in HEK-A(2B)-AdoR and NIH3T3 cells with K(B) values of 6 and 2 nM, respectively. In a single ascending-dose phase I clinical study, compound 62 had no serious adverse events and was well tolerated.

MeSH terms

  • Adenosine A2 Receptor Antagonists*
  • Animals
  • Binding Sites
  • Cell Line
  • Cyclic AMP / analysis
  • Dose-Response Relationship, Drug
  • Drug Design
  • Humans
  • Mice
  • Molecular Structure
  • NIH 3T3 Cells
  • Pulmonary Disease, Chronic Obstructive / drug therapy*
  • Rats
  • Stereoisomerism
  • Structure-Activity Relationship
  • Xanthines / chemical synthesis*
  • Xanthines / chemistry
  • Xanthines / pharmacology*


  • Adenosine A2 Receptor Antagonists
  • Xanthines
  • Cyclic AMP