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

摘要

In an effort to identify novel ligands possessing high affinity and selectivity for the A 2B 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 A _1 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 A _3 AR, and various degrees of selectivity toward A _1 and A _(2A) 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 A _(2A) AR, conferring high A _(2B)/A _(2A) AR selectivity. Derivative 13 (X = Cl, R = C 6H 5) is the most potent and selective compound, with an IC _(50) of 3.10 nM at A _(2B) AR and no affinity at A 1, A _(2A), and A _3 ARs.