2-[[(4-Amino-2-pyridyl)methyl]sulfinyl]benzimidazole H+/K+-ATPase inhibitors. The relationship between pyridine basicity, stability, and activity
| Autor: | Robert John Ife, Catherine A. Dyke, Eugene Meenan, David J. Keeling, Anthony H. Underwood, Colin J. Theobald, Carolyn A. Price, Michael E. Parsons, Malcolm L. Meeson |
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| Rok vydání: | 1989 |
| Předmět: |
Steric effects
Benzimidazole Chemical Phenomena Pyridines Stereochemistry ATPase Substituent Sulfenamide Gastric Acid H(+)-K(+)-Exchanging ATPase Structure-Activity Relationship chemistry.chemical_compound Dogs Nucleophile Drug Discovery Pyridine Animals Adenosine Triphosphatases biology Sulfoxide Rats Chemistry chemistry biology.protein Molecular Medicine Benzimidazoles Omeprazole |
| Zdroj: | Journal of Medicinal Chemistry. 32:1970-1977 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm00128a046 |
| Popis: | The benzimidazole sulfoxide class of antisecretory H+/K+-ATPase inhibitors need to possess high stability under neutral physiological conditions yet rearrange rapidly at low pH to the active sulfenamide 2. Since the initial reaction involves internal nucleophilic attack by the pyridine nitrogen, control of the pyridine pKa is critical. In this paper we show that by utilizing the powerful electron-donating effect of a 4-amino substituent on the pyridine, moderated by the electron-withdrawing effect of a 3- or 5-halogen substituent, a combination of high potency (as inhibitors of histamine-stimulated gastric acid secretion) and good stability under physiological conditions can be obtained. Furthermore, the role of the steric interaction between the 3/5-substituents and the 4-substituent in modifying the electron-donating ability of the 4-amino group is exemplified, and additional factors affecting stability are identified. One compound, in particular, 2-[[(3-chloro-4-morpholino-2- pyridyl)methyl]sulfinyl]-5-methoxy-(1H)-benzimidazole (3a, SK&F 95601), was chosen for further development and evaluation in man. |
| Databáze: | OpenAIRE |
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