Design, synthesis, and structure-activity relationships of novel 2-substituted pyrazinoylguanidine epithelial sodium channel blockers: drugs for cystic fibrosis and chronic bronchitis

J Med Chem. 2006 Jul 13;49(14):4098-115. doi: 10.1021/jm051134w.


Amiloride (1), the prototypical epithelial sodium channel (ENaC) blocker, has been administered with limited success as aerosol therapy for improving pulmonary function in patients with the genetic disorder cystic fibrosis. This study was conducted to synthesize and identify more potent, less reversible ENaC blockers, targeted for aerosol therapy and possessing minimal systemic renal activity. A series of novel 2-substituted acylguanidine analogues of amiloride were synthesized and evaluated for potency and reversibility on bronchial ENaC. All compounds tested were more potent and less reversible at blocking sodium-dependent short-circuit current than amiloride. Compounds 30-34 showed the greatest potency on ENaC with IC(50) values below 10 nM. A regioselective difference in potency was found (compounds 30, 39, and 40), whereas no stereospecific (compounds 33, 34) difference in potency on ENaC was displayed. Lead compound 32 was 102-fold more potent and 5-fold less reversible than amiloride and displayed the lowest IC(50) value ever reported for an ENaC blocker.

MeSH terms

  • Animals
  • Bronchi / drug effects
  • Bronchi / physiology
  • Bronchitis, Chronic / drug therapy*
  • Combinatorial Chemistry Techniques
  • Cystic Fibrosis / drug therapy*
  • Dogs
  • Epithelial Sodium Channels
  • Guanidines / chemical synthesis*
  • Guanidines / chemistry
  • Guanidines / pharmacology
  • Models, Molecular
  • Pyrazines / chemical synthesis*
  • Pyrazines / chemistry
  • Pyrazines / pharmacology
  • Respiratory Mucosa / drug effects
  • Respiratory Mucosa / physiology
  • Sodium Channel Blockers / chemical synthesis*
  • Sodium Channel Blockers / chemistry
  • Sodium Channel Blockers / pharmacology
  • Sodium Channels / drug effects*
  • Sodium Channels / physiology
  • Stereoisomerism
  • Structure-Activity Relationship
  • Tissue Culture Techniques


  • Epithelial Sodium Channels
  • Guanidines
  • N-(3,5-diamino-6-chloropyrazine-2-carbonyl)-N'-(4-(4-(2,3-dihydroxypropoxy)phenyl)butyl)guanidine
  • Pyrazines
  • Sodium Channel Blockers
  • Sodium Channels