New high affinity AT2 receptor ligands comprising a 2-methyl substituted phenylthiophene scaffold

A series of 2-substituted methylene imidazolephenylthiophene and tert-butylimidazolyl acetylphenylthiophene sulfonylcarbamate and sulfonamide derivatives were synthesized and assessed as AT₂R ligands. Substitution at this position of the phenyl ring, located between the thiophenyl and the linked imidazolyl substituent, has not previously been explored and unexpectedly resulted in significantly enhanced affinity for some of the new inhibitors. Introduction of a methyl group at the 2-position of the phenyl ring was found to markedly increase binding affinity to the AT₂R, as demonstrated across three different ligand classes. Binding affinities were improved by more than five-fold, while methoxy, bromo and fluoro substituents had only minor impacts on receptor binding. The most efficient ligands in the series, compounds 10 and 12, with K_i values of 1.9 and 0.97 nM, respectively, demonstrated >1000-fold selectivity over the the AT1 receptor and showed fair stability in human liver microsomes and human hepatocytes, but not in mouse liver microsomes. A tentative binding mode of inhibitor 12 was proposed after docking calculations.