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

A series of Et 4-amino-1-(2-chloro-2-phenylethyl)-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridine-5-carboxylates, e.g., I, has been synthesized as potential A1 adenosine receptor (A1 AR) ligands. Binding affinities of the compds. were detd. for adenosine A1, A2A and A3 receptors. Two of the compds. showed good affinity (Ki = 299 nM and 517 nM) and selectivity towards A1 AR, whereas some showed good affinity for A2A AR (Ki = 290 nM), higher than towards A1 AR (Ki = 1000 nM). The only arylamino deriv. of the series displayed high affinity (Ki = 4.6 nM) and selectivity for A3 AR. Mol. modeling and 3D-QSAR (CoMFA) studies carried out on the most active compds. gave further support to the pharmacol. results.