Selective angiotensin II AT2 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 frorn their capacity to induce neurite elongation in neuronal cells, as does angiotensin 11. (C) 2007 Elsevier Ltd. All rights reserved.