New non-peptide endothelin-A receptor antagonists: synthesis, biological properties, and structure-activity relationships of 5-(dimethylamino)-N-pyridyl-,-N-pyrimidinyl-,-N-pyridazinyl-, and -N-pyrazinyl-1-naphthalenesulfonamides

J Med Chem. 1997 Mar 14;40(6):996-1004. doi: 10.1021/jm9604585.


Use of automated synthesis led to the discovery of several 6-membered nitrogen heterocycles as replacements for the N-isoxazolyl substituent present in the 1-naphthalenesulfonamides endothelin-A (ETA) antagonist 5-(dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesu lfo namides (BMS 182874). In each of these heterocycles, a small substituent such as halogen para to the position of attachment to the sulfonamide nitrogen atom was found to be advantageous for ETA receptor affinity. Of these heterocycles, 2-pyrazines offered the greatest scope for improving receptor affinity. Optimization of the substituents at the 3- and 5-positions in the pyrazine ring led to potent, ETA-selective compounds such as 5-(dimethylamino)-N-(5-chloro-3-methoxy-2-pyrazinyl)-1- naphthalenesulfonamides (7m, ETA pIC50 8.1). When dosed orally at 10 mg/kg to conscious, normotensive rats infused with big ET-1, compounds such as 7m showed significant inhibition of the pressor response with a duration of effect lasting for the 5-h course of the experiment.

MeSH terms

  • Animals
  • Antihypertensive Agents / chemical synthesis*
  • Antihypertensive Agents / chemistry
  • Antihypertensive Agents / metabolism
  • Antihypertensive Agents / pharmacology
  • Blood Pressure / drug effects
  • Dansyl Compounds / chemical synthesis*
  • Dansyl Compounds / chemistry
  • Dansyl Compounds / metabolism
  • Dansyl Compounds / pharmacology*
  • Endothelin Receptor Antagonists*
  • Endothelin-1
  • Endothelins / antagonists & inhibitors
  • Endothelins / metabolism
  • Guinea Pigs
  • Magnetic Resonance Spectroscopy
  • Male
  • Molecular Structure
  • Protein Binding
  • Protein Precursors / antagonists & inhibitors
  • Protein Precursors / metabolism
  • Rats
  • Rats, Wistar
  • Receptor, Endothelin A
  • Receptors, Endothelin / metabolism
  • Structure-Activity Relationship


  • Antihypertensive Agents
  • Dansyl Compounds
  • Endothelin Receptor Antagonists
  • Endothelin-1
  • Endothelins
  • Protein Precursors
  • Receptor, Endothelin A
  • Receptors, Endothelin
  • 5-(dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesulfonamide