1,3-Dialkyl-8-(hetero)aryl-9-OH-9-deazaxanthines as potent A 2B adenosine receptor antagonists: Design, synthesis, structure–affinity and structure–selectivity relationships

Abstract

A number of 1,3-dialkyl-8-(hetero)aryl-9-OH-9-deazaxanthines were prepared and evaluated as ligands of recombinant human adenosine receptors ( hARs). Several 1,3-dipropyl derivatives endowed with nanomolar binding affinity at hA 2B receptors, but poor selectivity over hA 2A, hA 1 and hA 3 AR subtypes were identified. A comparison with the corresponding 7-OH- and 7,9-unsubstituted-deazaxanthines revealed that 9-OH-9-deazaxanthines are more potent hA 2B ligands with lower partition coefficients and higher water solubility compared to the other two congeneric classes of deazaxanthines. An optimization of the para-substituent of the 8-phenyl ring of 9-OH-9-deazaxanthines led to the discovery of compound 38, which exhibited outstanding hA 2B affinity (Ki = 1.0 nM), good selectivity over hA 2A, hA 1 and hA 3 (selectivity indices = 100, 79 and 1290, respectively) and excellent antagonist potency in a functional assay on rat A 2B (pA 2B = 9.33).