Nonpeptidic Angiotensin II Antagonists: Synthesis and in Vitro Activity of a Series of Novel Naphthalene and Tetrahydronaphthalene Derivatives

J Med Chem. 1991 Oct;34(10):3105-14. doi: 10.1021/jm00114a021.

Abstract

Starting from the structure of the novel nonpeptidic angiotensin II antagonist DuP 753, a series of more rigid analogues was prepared by replacing the biphenyl part of DuP 753 with a naphthalene ring. Five different regioisomers (compounds 6a-e) were synthesized, and receptor binding in rat smooth muscle cell preparations as well as inhibition of angiotensin II induced contraction of rabbit aortic rings was measured and the order of potency was compared with predictions made on the basis of a molecular modeling study. In good agreement with the predictions, the 2,6-substituted regioisomer 6d and its analogue 7 (isomeric at the imidazole substituent) were found to be most potent, but were still weaker than DuP 753. Tetrahydronaphthalene derivatives with and without an additional methyl group in the alpha-position to the acidic function and with this same 2,6-substitution pattern (compounds listed in Table III) were then prepared with the expectation of getting a further increase in potency. Whereas the carboxylic acid derivatives 13a,b showed activity in the expected potency range, surprisingly no further potency increase was observed after replacement of the carboxylic acid function by a tetrazole (compounds 18a,b). These results may indicate that the compounds do not bind to the AT1 receptor in the same way as DuP 753.

Publication types

  • Comparative Study

MeSH terms

  • Angiotensin II / antagonists & inhibitors*
  • Angiotensin Receptor Antagonists
  • Animals
  • Aorta, Thoracic
  • Biphenyl Compounds / chemistry*
  • Biphenyl Compounds / metabolism
  • Cells, Cultured
  • Imidazoles / chemistry*
  • Imidazoles / metabolism
  • Losartan
  • Male
  • Models, Molecular
  • Molecular Conformation
  • Muscle Contraction / drug effects
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / physiology
  • Naphthalenes / chemical synthesis*
  • Naphthalenes / metabolism
  • Naphthalenes / pharmacology
  • Rabbits
  • Rats
  • Receptors, Angiotensin / metabolism
  • Structure-Activity Relationship
  • Tetrahydronaphthalenes / chemical synthesis*
  • Tetrahydronaphthalenes / metabolism
  • Tetrahydronaphthalenes / pharmacology
  • Tetrazoles / chemistry*
  • Tetrazoles / metabolism

Substances

  • Angiotensin Receptor Antagonists
  • Biphenyl Compounds
  • Imidazoles
  • Naphthalenes
  • Receptors, Angiotensin
  • Tetrahydronaphthalenes
  • Tetrazoles
  • Angiotensin II
  • Losartan