Synthesis and 3D QSAR of new pyrazolo[3,4-b]pyridines:: Potent and selective inhibitors of A1 adenosine receptors

A number of 4-aminopyrazolo[3,4-b]pyridines 5-carboxylic acid esters (2-8) were synthesized and evaluated for their binding affinity at the A(1), A(2A), and A(3) adenosine receptors (AR), in bovine cortical membranes, as well as for their affinity toward human A(1)AR (hA(1)AR). Some of the new compounds were characterized by a high affinity and selectivity toward the A, receptor subtype, showing a significant improvement in comparison with other pyrazolo-pyridines previously reported in the literature. In particular the methyl ester 2h as well as the isopropyl ester 5h, both of them bearing a p-methoxyphenylethylamino side chain at the position 4, presented K-i values of 6 and 7 nM, respectively. To rationalize the relationships between structure and affinity of the novel compounds, a 3D QSAR model was also generated starting from compounds belonging to different classes of known A(1)AR antagonists.