Studies on (H(+)-K+)-ATPase inhibitors of gastric acid secretion. Prodrugs of 2-[(2-pyridinylmethyl)sulfinyl]benzimidazole proton-pump inhibitors

J Med Chem. 1991 Mar;34(3):1049-62. doi: 10.1021/jm00107a026.


The synthesis of N-substituted benzimidazole (H(+)-K+)-ATPase or proton-pump inhibitors is described. These compounds were prepared to function as prodrugs of the parent N-H compound and evaluated for their ability to inhibit gastric (H(+)-K+)-ATPase and gastric acid secretion. The prodrugs reported rely on either in vivo esterase hydrolysis for liberation of the parent compound (type I and type II) or require an acid environment for release of the active drug (type III and type IV). The N-(acyloxy)alkyl-substituted benzimidazoles 9, 11, and 24 showed improved chemical stability in the solid state and in aqueous solutions when compared to their parent N-H compounds. When given orally, 24 was found to be twice as potent as omeprazole in both the Shay rat and inactivation of gastric (H(+)-K+)-ATPase in the rat. The N-ethoxy-1-ethyl-substituted benzimidazoles 48-50 were found equally as effective as the N-H compound for inhibition of rat (H(+)-K+)-ATPase activity. In the Shay rat 48 at 10 mg/kg was approximately twice as active as parent timoprazole.

Publication types

  • Comparative Study

MeSH terms

  • 2-Pyridinylmethylsulfinylbenzimidazoles
  • Adenosine Triphosphatases / antagonists & inhibitors*
  • Animals
  • Benzimidazoles / chemical synthesis*
  • Benzimidazoles / metabolism
  • Benzimidazoles / pharmacology
  • Chemical Phenomena
  • Chemistry
  • Drug Stability
  • Esterases / metabolism
  • Female
  • Gastric Acid / metabolism*
  • Gastric Mucosa / enzymology
  • H(+)-K(+)-Exchanging ATPase
  • Hydrogen-Ion Concentration
  • Male
  • Molecular Structure
  • Omeprazole / pharmacology
  • Prodrugs / chemical synthesis*
  • Rabbits
  • Rats
  • Rats, Inbred Strains
  • Swine


  • 2-Pyridinylmethylsulfinylbenzimidazoles
  • Benzimidazoles
  • Prodrugs
  • timoprazole
  • Esterases
  • Adenosine Triphosphatases
  • H(+)-K(+)-Exchanging ATPase
  • Omeprazole