New pyrazolo[3,4-b]pyridones as selective A1 adenosine receptor antagonists: synthesis, biological evaluation and molecular modelling studies
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, A2A and A3 receptors. Compounds 5b and 5g showed good affinity (Ki = 299 nM and 517 nM, respectively) and selectivity towards A1 AR, whereas 5f showed good affinity for A2A AR (Ki = 290 nM), higher than towards A1 AR (Ki = 1000 nM). The only arylamino derivative of the series 5j displayed high affinity (Ki = 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.