3-Aryl-[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-one: a novel template for the design of highly selective A2B adenosine receptor antagonists

In an effort to identify novel ligands possessing high affinity and selectivity for the A2B AR subtype, we further investigated the class of 3-aryl[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-ones V, previously disclosed by us as selective A1 AR antagonists. Preliminary assays on a number of triazinobenzimidazoles derived from our "in-house" collection revealed that all the derivatives selected showed significant affinity at A 2B AR, no affinity at A3 AR, and various degrees of selectivity toward A1 and A2A ARs. Investigation of a new series featuring modified substituents at the 10-position (4′-chlorophenyl or phenylethyl groups), and a chlorine atom at the 7-position (X) of the triazinobenzimidazole nucleus, yielded highly potent and selective A 2B AR antagonists. The presence of a pendant 3-phenyl ring appears to hamper the interaction with A2A AR, conferring high A 2B/A2A AR selectivity. Derivative 13 (X = Cl, R = C 6H5) is the most potent and selective compound, with an IC50 of 3.10 nM at A2B AR and no affinity at A 1, A2A, and A3 ARs. © 2012 American Chemical Society.