(H+,K+)-ATPase inhibiting 2-[(2-pyridylmethyl)sulfinyl]benzimidazoles. 4. A novel series of dimethoxypyridyl-substituted inhibitors with enhanced selectivity. The selection of pantoprazole as a clinical candidate

J Med Chem. 1992 Mar 20;35(6):1049-57. doi: 10.1021/jm00084a010.


[(Pyridylmethyl)sulfinyl]benzimidazoles 1 (PSBs) are a class of highly potent antisecretory (H+,K+)-ATPase inhibitors which need to be activated by acid to form their active principle, the cyclic sulfenamide 4. Selective inhibitors of the (H+,K+)-ATPase in vivo give rise to the nonselective thiophile 4 solely at low pH, thus avoiding interaction with other thiol groups in the body. The propensity to undergo the acid-catalyzed transformation is dependent on the nucleophilic/electrophilic properties of the functional groups involved in the formation of 2 since this step is both rate-determining and pH-dependent. The aim of this study was to identify compounds with high (H+,K+)-ATPase inhibitory activity in stimulated gastric glands possessing acidic pH, but low reactivity (high chemical stability) at neutral pH as reflected by in vitro (Na+,K+)-ATPase inhibitory activity. The critical influence of substituents flanking the pyridine 4-methoxy substituent present in all derivatives was carefully studied. The introduction of a 3-methoxy group gave inhibitors possessing a combination of high potency, similar to omeprazole and lansoprazole, but increased stability. As a result of these studies, compound 1a (INN pantoprazole) was selected as a candidate drug and is currently undergoing phase III clinical studies.

MeSH terms

  • 2-Pyridinylmethylsulfinylbenzimidazoles
  • Adenosine Triphosphatases / antagonists & inhibitors*
  • Adenosine Triphosphate / antagonists & inhibitors
  • Animals
  • Benzimidazoles / chemical synthesis*
  • Benzimidazoles / chemistry
  • Benzimidazoles / pharmacology*
  • Dogs
  • Gastric Mucosa / drug effects
  • H(+)-K(+)-Exchanging ATPase
  • Omeprazole / analogs & derivatives
  • Pantoprazole
  • Pyridines / chemical synthesis*
  • Pyridines / chemistry
  • Pyridines / pharmacology
  • Rabbits
  • Structure-Activity Relationship
  • Sulfoxides / pharmacology*


  • 2-Pyridinylmethylsulfinylbenzimidazoles
  • Benzimidazoles
  • Pyridines
  • Sulfoxides
  • Adenosine Triphosphate
  • Pantoprazole
  • Adenosine Triphosphatases
  • H(+)-K(+)-Exchanging ATPase
  • Omeprazole