Nonpeptide angiotensin II receptor antagonists: the discovery of a series of N-(biphenylylmethyl)imidazoles as potent, orally active antihypertensives

J Med Chem. 1991 Aug;34(8):2525-47. doi: 10.1021/jm00112a031.


A new series of nonpeptide angiotensin II (AII) receptor antagonists has been prepared. These N-(biphenylyl-methyl)imidazoles, e.g. 2-butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-4-chloro-5- (hydroxymethyl)imidazole, differ from the previously reported N-(benzamidobenzyl)imidazoles and related compounds in that they produce a potent antihypertensive effect upon oral administration; the earlier series generally were active only when administered intravenously. It has been found that the acidic group at the 2'-position of the biphenyl is essential. Only ortho-substituted acids possess both high affinity for the AII receptor and good oral antihypertensive potency. The carboxylic acid group has been replaced with a variety of acidic isosteres, and the tetrazole ring has been found to be the most effective. The tetrazole derivative, DuP 753, is currently in development for the treatment of hypertension.

MeSH terms

  • Administration, Oral
  • Adrenal Glands / metabolism
  • Angiotensin Receptor Antagonists*
  • Animals
  • Antihypertensive Agents / chemical synthesis*
  • Antihypertensive Agents / therapeutic use
  • Biphenyl Compounds / chemical synthesis*
  • Biphenyl Compounds / metabolism
  • Biphenyl Compounds / therapeutic use
  • Chemical Phenomena
  • Chemistry
  • Hypertension / drug therapy
  • Imidazoles / chemical synthesis*
  • Imidazoles / metabolism
  • Imidazoles / therapeutic use
  • Losartan
  • Male
  • Molecular Structure
  • Rats
  • Rats, Inbred Strains
  • Receptors, Angiotensin / metabolism
  • Structure-Activity Relationship
  • Tetrazoles / chemical synthesis
  • Tetrazoles / therapeutic use


  • Angiotensin Receptor Antagonists
  • Antihypertensive Agents
  • Biphenyl Compounds
  • Imidazoles
  • Receptors, Angiotensin
  • Tetrazoles
  • Losartan