Conformationally Restricted Polysubstituted Biphenyl Derivatives With Angiotensin II Receptors Antagonist Properties

J Med Chem. 1991 Aug;34(8):2410-4. doi: 10.1021/jm00112a015.

Abstract

The synthesis and in vitro activity of new nonpeptide angiotensin II antagonists is presented. Compared to previously reported biphenyl compounds, the new analogues 8 and 9 have reduced conformational freedom derived from steric hindrance. Methyl 4'-methyl-2',6'-dimethoxy[1,1'-biphenyl]-2-carboxylate 4 has been synthesized by a Von Pechmann condensation of orcinol with oxocyclohexane-2-carboxylate followed by dehydrogenation. This scheme provided the carbon skeleton of the biphenyl potentially substituted on the 2-, 2'-, 4'-, and 6'-positions. Elaboration of the subsituents led to a biphenyl derivative used to alkylate a 2-n-butyl-4-chloro-5-(hydroxymethyl)imidazole. After coupling with the imidazole two regioisomers were separated and identified by 1H NMR. NOESY experiments were useful to establish regiochemistry of the final products that have angiotensin II blocking activity. Their affinity for angiotensin II receptors was established in a binding assay experiment and in an isolated organ test. The presence of 2',6'-dimethoxy substituent on the biphenyl moiety of the antagonist was found to significantly decrease affinity for the receptor.

MeSH terms

  • Angiotensin II / antagonists & inhibitors*
  • Angiotensin II / metabolism
  • Angiotensin Receptor Antagonists
  • Animals
  • Aorta / drug effects
  • Aorta / physiology
  • Binding, Competitive
  • Biphenyl Compounds / chemistry*
  • Biphenyl Compounds / metabolism
  • Biphenyl Compounds / pharmacology
  • Chemical Phenomena
  • Chemistry
  • Female
  • Imidazoles / chemistry*
  • Imidazoles / metabolism
  • Imidazoles / pharmacology
  • Male
  • Molecular Conformation
  • Muscle Contraction / drug effects
  • Muscle, Smooth / drug effects
  • Muscle, Smooth / physiology
  • Rabbits
  • Rats
  • Rats, Inbred Strains
  • Receptors, Angiotensin / metabolism
  • Uterus / metabolism

Substances

  • Angiotensin Receptor Antagonists
  • Biphenyl Compounds
  • Imidazoles
  • Receptors, Angiotensin
  • Angiotensin II
  • 4'-((2-butyl-4-(hydroxymethyl)-5-chloro-1H-imidazolyl)methyl)-2',6'-dimethoxy(1,1'-biphenyl)-2-carboxylic acid
  • 4'-((2-butyl-4-chloro-5-(hydroxymethyl)-1H-imidazolyl)methyl)-2',6'-dimethoxy(1,1'-biphenyl)-2-carboxylic acid