New nonpeptide angiotensin II receptor antagonists. 2. Synthesis, biological properties, and structure-activity relationships of 2-alkyl-4-(biphenylylmethoxy)quinoline derivatives

J Med Chem. 1992 Oct 30;35(22):4027-38. doi: 10.1021/jm00100a007.


A novel series of nonpeptidic angiotensin II (AII) receptor antagonists is reported, derived from linkage of the biphenylcarboxylic acid or biphenylyltetrazole moiety found in previously described antagonists via a methyleneoxy chain to the 4-position of a 2-alkyl quinoline. When evaluated in an in vitro binding assay using a guinea pig adrenal membrane preparation, compounds in this series generally gave IC50 values in the range 0.01-1 microM. Structure-activity studies showed the quinoline nitrogen atom and a short alkyl chain at the quinoline 2-position to be essential for receptor binding. On intravenous administration in a normotensive rat model, the more potent compounds inhibited the AII-induced pressor response with ED50 values in the range 0.1-2.0 mg/kg. One of the compounds, 2-ethyl-4-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methoxy]quinoline (5g), demonstrated good oral activity in two rat models. At doses in the range 1-10 mg/kg in AII-infused, normotensive rats, the compound exhibited a dose-related inhibition of the pressor response with a good duration of action at the higher doses. In a renal hypertensive rat model, compound 5g showed a rapid and sustained lowering of blood pressure at a dose of 5 mg/kg. On the basis of its profile, this compound, designated ICI D8731, has been selected for clinical evaluation.

MeSH terms

  • Angiotensin II / antagonists & inhibitors
  • Angiotensin Receptor Antagonists*
  • Animals
  • Antihypertensive Agents / chemical synthesis*
  • Antihypertensive Agents / chemistry
  • Antihypertensive Agents / pharmacology
  • Binding, Competitive
  • Blood Pressure / drug effects
  • Dose-Response Relationship, Drug
  • Guinea Pigs
  • Hydrogen Bonding
  • Hypertension, Renal / physiopathology
  • In Vitro Techniques
  • Male
  • Models, Molecular
  • Molecular Conformation
  • Quinolines / chemical synthesis*
  • Quinolines / chemistry
  • Quinolines / metabolism
  • Quinolines / pharmacology
  • Radioligand Assay
  • Rats
  • Rats, Wistar
  • Receptors, Angiotensin / metabolism
  • Structure-Activity Relationship
  • X-Ray Diffraction


  • Angiotensin Receptor Antagonists
  • Antihypertensive Agents
  • Quinolines
  • Receptors, Angiotensin
  • Angiotensin II