Potent Nonpeptide Angiotensin II Receptor Antagonists. 2. (1-Carboxybenzyl)imidazole-5-acrylic Acids

Article abstract of DOI:10.1021/jm00065a011

The further evolution of the imidazole-5-acrylic acid series of nonpeptide angiotensin II receptor antagonists is detailed (for Part 1, see: J.Med.Chem. 1992, 35, 3858).Modifications of the N-benzyl ring substitution were undertaken in an effort to mimic the Tyr⁴ residue of angiotensin II.Introduction of a p-carboxylic acid on the N-benzyl ring resulted in the discovery of compounds with nanomolar affinity for the receptor and good oral activity.SAR studies of these potent antagonists revealed that the thienyl ring, the (E)-acrylic acid, and the imidazole ring in addition to the two acid groups were important for high potency.Also, overlay comparisons of the parent diacid with both angiotensin II and a representative biphenylyltetrazole nonpeptide angiotensin II receptor antagonist are presented.The parent diacid analog, SK<*>F 108566 or (E)-3-<2-butyl-1-(4-carboxybenzyl)-1H-imidazol-5-yl>-2-<(2-thienyl)methyl>propenoic acid, is currently in clinical development for the treatment of hypertension.