New pyrazolo[3,4-b]pyridones as selective A1 adenosine receptor antagonists: synthesis, biological evaluation and molecular modelling studies

Abstract

A series of ethyl 4-amino-1-(2-chloro-2-phenylethyl)-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridine-5-carboxylates (5a–j) has been synthesized as potential A₁ adenosine receptor (A₁ AR) ligands. Binding affinities of the new compounds were determined for adenosine A₁, A_2A and A₃ receptors. Compounds 5b and 5g showed good affinity (K_i = 299 nM and 517 nM, respectively) and selectivity towards A₁ AR, whereas 5f showed good affinity for A_2A AR (K_i = 290 nM), higher than towards A₁ AR (K_i = 1000 nM). The only arylamino derivative of the series 5j displayed high affinity (K_i = 4.6 nM) and selectivity for A₃ AR. Molecular modelling and 3D-QSAR (CoMFA) studies carried out on the most active compounds gave further support to the pharmacological results.