N-(Heteroaryl)thiophene sulfonamides as angiotensin AT2 receptor ligands

Two series of N-(heteroaryl)thiophene sulfonamides, encompassing either a methylene imidazole group or a tert-butylimidazolylacetyl group in the meta position of the benzene ring, have been synthesized. An AT₂R selective ligand with a K_i of 42 nM was identified in the first series and in the second series, six AT₂R selective ligands with significantly improved binding affinities and K_i values of <5 nM were discovered. The binding modes to AT₂R were explored by docking calculations combined with molecular dynamics simulations. Although some of the high affinity ligands exhibited fair stability in human liver microsomes, comparable to that observed with C21 undergoing clinical trials, most ligands displayed a very low metabolic stability with t_½ of less than 10 min in human liver microsomes. The most promising ligand, with an AT₂R K_i value of 4.9 nM and with intermediate stability in human hepatocytes (t_½ = 77 min) caused a concentration-dependent vasorelaxation of pre-contracted mouse aorta.