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

J Med Chem. 1992 Oct 16;35(21):3858-72. doi: 10.1021/jm00099a013.

Abstract

A series of 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.

MeSH terms

  • Acrylates / chemistry
  • Acrylates / pharmacology*
  • Angiotensin Receptor Antagonists*
  • Animals
  • Drug Design
  • Imidazoles / chemistry
  • Imidazoles / pharmacology*
  • In Vitro Techniques
  • Male
  • Rabbits
  • Radioligand Assay
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship
  • X-Ray Diffraction

Substances

  • Acrylates
  • Angiotensin Receptor Antagonists
  • Imidazoles