| Autor: |
Sih JC; Research Laboratories, Upjohn Company, Kalamazoo, Michigan 49001., Im WB, Robert A, Graber DR, Blakeman DP |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 1991 Mar; Vol. 34 (3), pp. 1049-62. |
| DOI: |
10.1021/jm00107a026 |
| Abstrakt: |
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: |
MEDLINE |
| Externí odkaz: |
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