Reversible inhibitors of the gastric (H+/K+)-ATPase. 4. Identification of an inhibitor with an intermediate duration of action
| Autor: | Robert John Ife, Leach Colin Andrew, Kenneth Wiggall, Thomas Henry Brown, Michael E. Parsons, Colin J. Theobald, David J. Keeling |
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| Rok vydání: | 1995 |
| Předmět: |
chemistry.chemical_classification
Magnetic Resonance Spectroscopy Time Factors Bicyclic molecule biology Stereochemistry Quinoline Stomach Proton Pump Inhibitors H(+)-K(+)-Exchanging ATPase Chemical synthesis chemistry.chemical_compound Structure-Activity Relationship Enzyme chemistry Enzyme inhibitor Drug Discovery medicine biology.protein Quinolines Molecular Medicine Potency Omeprazole medicine.drug |
| Zdroj: | Journal of medicinal chemistry. 38(14) |
| ISSN: | 0022-2623 |
| Popis: | 3-Acyl-4-(arylamino)quinolines were previously identified as gastric (H + /K + )-ATPase inhibitors, and clinical efficacy has been demonstrated for compound 3 (SK&F 96067). In the present study the further structure-activity relationship of this series is developed. Only a limited range of substituents are tolerated on the N-aryl ring or the 6- and 7-positions of the quinoline, and although hydroxylated derivatives were identified possessing markedly greater affinity for the enzyme, none of these proved to have adequate potency after oral dosing. In contrast, the 8-position of the quinoline ring proved suitable for a wide variety of substituents, allowing modification of physicochemical properties while retaining primary activity. This led to the identification of compound 4 (SK&F 97574), which combines good oral potency with a somewhat longer duration of action than 3 (though much shorter than covalent inhibitors such as omeprazole). This compound was selected for further development and evaluation in man. |
| Databáze: | OpenAIRE |
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