Discovery of novel A3 adenosine receptor ligands based on chromone scaffold

A project focused on the discovery of new chemical entities (NCEs) as AR ligands that incorporate a benzo-gamma-pyrone [(4H)-1-benzopyran-4-one] substructure has been developed. Accordingly, two series of novel chromone carboxamides placed at positions C2 (compounds 2-13) and C3 (compounds 15-26) of the gamma-pyrone ring were synthesized using chromone carboxylic acids (compounds 1 or 14) as starting materials. From this study and on the basis of the obtained structure-activity relationships it was concluded that the chromone carboxamide scaffold represent a novel class of AR ligands. The most remarkable chromones were compounds 21 and 26 that present a better affinity for A(3)AR (K-i = 3680 nM and K-i = 3750 nM, respectively). Receptor-driven molecular modeling studies provide information on the binding/selectivity data of the chromone. The data so far acquired are instrumental for future optimization of chromone carboxamide as a selective A(3)AR antagonist. (c) 2012 Elsevier Inc. All rights reserved.