Synthesis and 3D QSAR of New Pyrazolo[3,4-b]pyridines:Potent and Selective Inhibitors of AI Adenosine Receptors

摘要

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_1AR(hA_1AR).Some of the new compounds were characterized by a high affinity and selectivity toward the AI 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_1AR antagonists.