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 (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 N-3-R) on A(2B)-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-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.