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We here report on our continued studies of ligands binding to the promising drug target angiotensin II type 2 receptor (AT 2 R). Two series of compounds were synthesized and investigated. The first series explored the effects of adding small substituents to the phenyl ring of the known selective nonpeptide AT 2 R antagonist  C38 , generating small but significant shifts in AT 2 R affinity. One compound in the first series was equipotent to  C38  and showed similar kinetic solubility, and stability in both human and mouse liver microsomes. The second series was comprised of new bicyclic derivatives, amongst which one ligand exhibited a five‐fold improved affinity to AT 2 R as compared to  C38 . The majority of the compounds in the second series, including the most potent ligand, were inferior to  C38  with regard to stability in both human and mouse microsomes. In contrast to our previously reported findings, ligands with shorter carbamate alkyl chains only demonstrated slightly improved stability in microsomes. Based on data presented herein, a more adequate, tentative model of the binding modes of ligand analogues to the prototype AT 2 R antagonist  C38  is proposed, as deduced from docking redefined by molecular dynamic simulations.

A Series of Analogues to the AT 2 R Prototype Antagonist C38 Allow Fine Tuning of the Previously Reported Antagonist Binding Mode