Studies on (H(+)-K+)-ATPase inhibitors of gastric acid secretion. Prodrugs of 2-[(2-pyridinylmethyl)sulfinyl]benzimidazole proton-pump inhibitors
| Autor: | Wha Bin Im, David R. Graber, John C. Sih, David P. Blakeman, André Robert |
|---|---|
| Rok vydání: | 1991 |
| Předmět: |
Male
Benzimidazole Chemical Phenomena Stereochemistry Swine ATPase 2-Pyridinylmethylsulfinylbenzimidazoles Gastric Acid chemistry.chemical_compound H(+)-K(+)-Exchanging ATPase Drug Stability Drug Discovery Animals Prodrugs Adenosine Triphosphatases Timoprazole biology Molecular Structure Chemistry Esterases Biological activity Rats Inbred Strains Prodrug Hydrogen-Ion Concentration Rats Enzyme inhibitor Gastric Mucosa biology.protein Molecular Medicine Liberation Gastric acid Benzimidazoles Female Rabbits Omeprazole |
| Zdroj: | Journal of medicinal chemistry. 34(3) |
| ISSN: | 0022-2623 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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