Introduction of a 2-methyl group on the phenyl ring yielded highly efficient AT2 receptor ligands (compounds 10 and 12) with Ki values of 1.9 and 0.97 nM and >1000-fold selectivity over AT1.
Introduction of a methyl group at the 2-position of the phenyl ring in these new ligands significantly enhanced AT2 receptor binding affinity and selectivity.
A series of 2-substituted methylene imidazolephenylthiophene and tert -butylimidazolyl acetylphenylthiophene sulfonylcarbamate and sulfonamide derivatives were synthesized and assessed as AT 2 R 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 AT 2 R, 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.
Gising et al. (Fri,) reported a other. 2-methyl substituted phenylthiophene scaffold derivatives was evaluated on Binding affinity to AT2R. Introduction of a 2-methyl group on the phenyl ring yielded highly efficient AT2 receptor ligands (compounds 10 and 12) with Ki values of 1.9 and 0.97 nM and >1000-fold selectivity over AT1.