Selective angiotensin II AT2 receptor agonists:: Arylbenzylimidazole structure-activity relationships

Structural alterations in the 2- and 5-positions of the first drug-like selective angiotensin II AT(2) receptor agonist (1) have been performed. The imidazole ring system was proven to be a strong determinant for the AT(2) selectivity, and with few exceptions all variations gave good AT(2) receptor affinities and with retained high AT(2)/AT(1) selectivities. On the contrary to the findings with AT(1) receptor agonists, the impact of structural modifications in the 5-position of the AT(2) selective compounds were less pronounced regarding activation of the AT(2) receptor. The butyloxyphenyl (56) and the propylthienyl (50) derivatives were found to exert a high agonistic effect as deduced from their capacity to induce neurite elongation in neuronal cells, as does angiotensin II.