Selective angiotensin II AT ₂ receptor agonists devoid of the imidazole ring system

A versatile parallel synthetic method to obtain three series of non-cyclic analogues of the first drug-like selective angiotensin II AT ₂ receptor agonist (1) has been developed. In analogy with the transformation of losartan to valsartan it was demonstrated that a non-cyclic moiety could be employed as an imidazole replacement to obtain AT ₂ selective compounds. In all the three series, AT ₂ receptor ligands with affinities in the lower nanomolar range were found. None of the analogues exhibited any affinity for the AT ₁ receptor. Four compounds, 17, 22, 39 and 51, were examined in a neurite outgrowth cell assay. All four compounds were found to exert a high agonistic effect as deduced from their capacity to induce neurite elongation in neuronal cells, as does angiotensin II.