2-Alkyl substituted benzimidazoles as a new class of selective AT2 receptor ligands

Ligands comprising a benzimidazole rather than the imidazole ring that is common in AT₂R ligands e.g. in the AT₂R agonist C21, can provide both high affinity and receptor selectivity. In particular, compounds encompassing benzimidazoles, substituted in the 2-position with small bulky groups such as an isopropyl (K_i = 4.0 nM) or a tert-butyl (K_i = 5.3 nM) or alternatively a thiazole heterocycle (K_i = 5.1 nM) demonstrate high affinity and AT₂R selectivity. An n-butyl chain, as found in the AT₁R selective sartans, makes the ligand less receptor selective. The isobutyl group on the biaryl scaffold present in most AT₂R selective ligands reported so far was originally derived from the nonselective potent AT₁R/AT₂R ligand L-162,313. Notably, in all ligands discussed herein, the isobutyl group was substituted by an n-propyl group and ligands with high affinity to AT₂R were provided and in addition the majority of them demonstrate a favorable AT₂R/AT₁R selectivity. The introduction of fluoro atoms in various positions had no pronounced effect on the affinity data. Ligands with a thiazole or a tert-butyl group attached to the 2-position and with a terminal trifluoromethyl butoxycarbonyl sidechain exhibited a similar stability as C21 in human liver microsomes, while other ligands examined were less stable in the microsome assay.