Discovery of N-isoxazolyl biphenylsulfonamides as potent dual angiotensin II and endothelin A receptor antagonists

J Med Chem. 2002 Aug 29;45(18):3829-35. doi: 10.1021/jm020138n.

Abstract

The ET(A) receptor antagonist (2) (N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)-[1,1'-biphenyl]-2-sulfonamide, BMS-193884) shares the same biphenyl core as a large number of AT(1) receptor antagonists, including irbesartan (3). Thus, it was hypothesized that merging the structural elements of 2 with those of the biphenyl AT(1) antagonists (e.g., irbesartan) would yield a compound with dual activity for both receptors. This strategy led to the design, synthesis, and discovery of (15) (4'-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-N-(3,4-dimethyl-5-isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl]-[1,1'-biphenyl]-2-sulfonamide, BMS-248360) as a potent and orally active dual antagonist of both AT(1) and ET(A) receptors. Compound 15 represents a new approach to treating hypertension.

MeSH terms

  • Angiotensin II / metabolism*
  • Angiotensin Receptor Antagonists*
  • Animals
  • Antihypertensive Agents / chemical synthesis
  • Antihypertensive Agents / chemistry
  • Antihypertensive Agents / pharmacology
  • Blood Pressure / drug effects
  • CHO Cells
  • Cricetinae
  • Crystallography, X-Ray
  • Endothelin Receptor Antagonists*
  • Isoxazoles / chemical synthesis*
  • Isoxazoles / chemistry
  • Isoxazoles / pharmacology
  • Molecular Structure
  • Radioligand Assay
  • Rats
  • Receptor, Angiotensin, Type 1
  • Receptor, Endothelin A
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology

Substances

  • Angiotensin Receptor Antagonists
  • Antihypertensive Agents
  • BMS 248360
  • Endothelin Receptor Antagonists
  • Isoxazoles
  • Receptor, Angiotensin, Type 1
  • Receptor, Endothelin A
  • Sulfonamides
  • Angiotensin II