Detalle de: N-(Methyloxycarbonyl)thiophene sulfonamides as high affinity AT2 receptor ligands

A series of meta-substituted acetophenone derivatives, encompassing N-(alkyloxycarbonyl)thiophene sulfonamide fragments have been synthesized. Several selective AT2 receptor ligands were identified, among those a tert-butylimidazole derivative (20) with a K i of 9.3 nM, that demonstrates a high stability in human liver microsomes (t ½ = 62 min) and in human hepatocytes (t ½ = 194 min). This methyloxycarbonylthiophene sulfonamide is a 20-fold more potent binder to the AT2 receptor and is considerably more stable in human liver microsomes, than a previously reported and broadly studied structurally related AT 2 R prototype antagonist 3 (C38). Ligand 20 acts as an AT 2 R agonist and caused an AT 2 R mediated concentration-dependent vasorelaxation of pre-contracted mouse aorta. Furthermore, in contrast to imidazole derivative C38, the tert-butylimidazole derivative 20 is a poor inhibitor of CYP3A4, CYP2D6 and CYP2C9. It is demonstrated herein that smaller alkyloxycarbonyl groups make the ligands in this series of AT 2 R selective compounds less prone to degradation and that a high AT2 receptor affinity can be retained after truncation of the alkyloxycarbonyl group. Binding modes of the most potent AT 2 R ligands were explored by docking calculations combined with molecular dynamics simulations.