6-Substituted benzimidazoles as new nonpeptide angiotensin II receptor antagonists: synthesis, biological activity, and structure-activity relationships

J Med Chem. 1993 Dec 10;36(25):4040-51. doi: 10.1021/jm00077a007.


Starting from the recently reported nonpeptidic angiotensin II (AII) receptor antagonists DuP753 (1) and Exp 7711 (2), we have designed and investigated novel substituted benzimidazoles. Systemic variation of several substituents at the benzimidazole ring positions 4-7 led to the finding that substitution in position 6 with acylamino groups results in highly active AII antagonists. Compounds with 6-membered lactam or sultam substituents in position 6 of benzimidazole showed receptor activities in the low nanomolar range but were only weakly active when given orally to rats. In contrast, analogous substitution of the benzimidazole moiety with basic heterocycles resulted in potent AII antagonists which were also well absorbed after oral application. The most active compound of this series, 33 (BIBR 277), was selected as a candidate for clinical development. On the basis of molecular modeling studies a binding model of this new class of AII antagonists to the AT1 receptor is proposed.

MeSH terms

  • Angiotensin II / antagonists & inhibitors*
  • Angiotensin Receptor Antagonists*
  • Animals
  • Benzimidazoles / chemical synthesis*
  • Benzimidazoles / chemistry
  • Benzimidazoles / pharmacology*
  • Benzoates / chemical synthesis
  • Benzoates / chemistry
  • Benzoates / pharmacology*
  • Binding Sites / drug effects
  • Blood Pressure / drug effects
  • Male
  • Models, Molecular
  • Rats
  • Rats, Wistar
  • Receptors, Angiotensin / metabolism
  • Structure-Activity Relationship
  • Telmisartan


  • Angiotensin Receptor Antagonists
  • Benzimidazoles
  • Benzoates
  • Receptors, Angiotensin
  • Angiotensin II
  • Telmisartan