4-(Heteroarylthio)-2-biphenylyltetrazoles as nonpeptide angiotensin II antagonists

J Med Chem. 1995 Nov 10;38(23):4670-8. doi: 10.1021/jm00023a006.

Abstract

A series of 4-(heteroarylthio)-2-biphenylyltetrazoles was prepared, and the compounds were examined for their ability to displace [3H]AII from angiotensin II receptors. Analogues that exhibited significant receptor binding affinities at less than 10 microM were investigated further for potential antagonism of angiotensin II-mediated contraction of rabbit isolated aortic rings. Three 4-(heteroarylthio)-2-biphenylyltetrazoles were identified that exhibited sub-micromolar angiotensin II receptor binding affinities. These compounds and two reference agents, saralasin and losartan (DUP-753), exhibited concentration-dependent reversal of angiotensin II contraction in isolated aortic rings parallel to their receptor binding affinities. Molecular modeling studies were conducted to examine the conformational effects of the novel sulfide bridging unit contained in these 4-(heteroarylthio)-2-biphenylyltetrazoles. The biological effects of the sulfide bridge as well as alterations in the heteroaromatic moiety were investigated, and the resulting structure--activity relationships are discussed.

Publication types

  • Comparative Study

MeSH terms

  • Angiotensin II / antagonists & inhibitors*
  • Angiotensin II / metabolism
  • Angiotensin II / pharmacology
  • Angiotensin Receptor Antagonists
  • Animals
  • Aorta, Abdominal / drug effects
  • Aorta, Abdominal / physiology
  • Binding, Competitive
  • Biphenyl Compounds / pharmacology
  • Imidazoles / pharmacology
  • Losartan
  • Male
  • Models, Molecular
  • Muscle Contraction / drug effects
  • Naphthyridines / chemical synthesis*
  • Naphthyridines / metabolism
  • Naphthyridines / pharmacology
  • Quinolines / chemical synthesis*
  • Quinolines / metabolism
  • Quinolines / pharmacology
  • Rabbits
  • Radioligand Assay
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Angiotensin / metabolism
  • Saralasin / pharmacology
  • Structure-Activity Relationship
  • Sulfides / chemistry
  • Tetrazoles / chemical synthesis*
  • Tetrazoles / metabolism
  • Tetrazoles / pharmacology

Substances

  • 2-ethyl-4-((2'-(1H-tetrazol-5-yl)-4-biphenylyl)thio)-1,5-naphthyridine
  • 2-methyl-4-((2'-(1H-tetrazol-5-yl)-4-biphenylyl)thio)quinoline
  • Angiotensin Receptor Antagonists
  • Biphenyl Compounds
  • Imidazoles
  • Naphthyridines
  • Quinolines
  • Receptors, Angiotensin
  • Sulfides
  • Tetrazoles
  • Angiotensin II
  • Saralasin
  • Losartan