Discovery of a Novel A2B Adenosine Receptor Antagonist as a Clinical Candidate for Chronic Inflammatory Airway Diseases

Recently, we have reported a series of new 1,3-symmetrically (R1 = R3) substituted xanthines (3 and 4) which have high affinity and selectivity for the human adenosine A2B receptors (hA2B-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 ≠ N 3-R) on A2B-AdoR affinity and selectivity; we had the dual objectives of enhancing affinity and selectivity for the A2B−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 hA2B-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-A2B-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.