| Autor: |
Ugarkar, B. G., DaRe, J. M., Kopcho, J. J., Browne, C. E., III, Schanzer, J. M., Wiesner, J. B., Erion, M. D. |
| Zdroj: |
Journal of Medicinal Chemistry; July 27, 2000, Vol. 43 Issue: 15 p2883-2893, 11p |
| Abstrakt: |
Adenosine receptor agonists produce a wide variety of therapeutically useful pharmacologies. However, to date they have failed to undergo successful clinical development due to dose-limiting side effects. Adenosine kinase inhibitors (AKIs) represent an alternative strategy, since AKIs may raise local adenosine levels in a more site- and event-specific manner and thereby elicit the desired pharmacology with a greater therapeutic window. Starting with 5-iodotubercidin (IC50 = 0.026 μM) and 5-amino-5-deoxyadenosine (IC50 = 0.17 μM) as lead inhibitors of the isolated human AK, a variety of pyrrolo[2,3-d]pyrimidine nucleoside analogues were designed and prepared by coupling 5-substituted-4-chloropyrrolo[2,3-d]pyrimidine bases with ribose analogues using the sodium salt-mediated glycosylation procedure. 5-Amino-5-deoxy analogues of 5-bromo- and 5-iodotubercidins were found to be the most potent AKIs reported to date (IC50s < 0.001 μM). Several potent AKIs were shown to exhibit anticonvulsant activity in the rat maximal electric shock (MES) induced seizure assay. |
| Databáze: |
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