2,6,8-trisubstituted 1-deazapurines as adenosine receptor antagonists

In this study we developed a refined pharmacophore model for antagonists of the human adenosine A(1) receptor, based on features of known pyrimidine and purine derivatives. The adoption of these updated criteria assisted us in synthesizing a series of 1-deazapurines with consistently high affinity as inverse agonists for the adenosine A(1) receptor. These 1-deazapurines (otherwise known as 3H-imidazo[4,5-b]pyridines) were substituted at their 2- and 6-positions, yielding a series with five of the derivatives displaying K-i values in the subnanomolar range. The most potent of these, compound 10 (LUF 5978), displayed an affinity of 0.55 nM at the human adenosine A(1) receptor with > 300-fold and 45-fold selectivity toward A(2A) and A(3) receptors, respectively. Compound 14 (LUF 5981, K-i = 0.90 nM) appeared to have the best overall selectivity with respect to adenosine A(2A) (> 200-fold) and A(3) (700-fold) receptors.