Imidazole-5-acrylic Acids: Potent Nonpeptide Angiotensin II Receptor Antagonists Designed Using a Novel Peptide Pharmacophore Model

Article abstract of DOI:10.1021/jm00099a013

A series a novel nonpeptide angiotensin II receptor antagonists containing a substituted (E)-acrylic acid has been developed.The overlay of 1, an imidazole-5-acetic acid found in the patent literature, on a novel pharmacophore model of AII suggested that extension of the acid side chain and attachment of a second aryl residue to mimic the C-terminal phenylalanine region of AII would lead to increased activity.A study of extended acid side chains at C-5 of the imidazole nucleus led to the discovery of the (E)-acrylic acid 5 as a promising starting point for further exploration.As predicted by the modeling, substitution of a benzyl group on the acrylic acid side chain to mimic the phenylalanine gave increased potency.An extensive study of the SAR of the newly introduced aromatic ring revealed that electron-rich heteroaryl rings provided improved activity, most notably in the in vivo rat models.Compound 40, (E)-3-<2-butyl-1-<(2-chlorophenyl)methyl>imidazol-5-yl>-2-<(2-thienyl)methyl>-2-propenoic acid, has been shown to be a potent, competitive, and orally active small molecule AT-1 receptor antagonist.It exhibits a 2 orders of magnitude increase in binding affinity and a 10-fold improvement in in vivo potency as compared to compound 1 and represents an important milestone in the development of even more potent nonpeptide angiotensin II receptor antagonists.