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- Title
Design and Synthesis of Imidazopyrazolopyridines as Novel Selective COX-2 Inhibitors.
- Authors
Badrey, Mohamed G.; Abdel-Aziz, Hassan M.; Gomha, Sobhi M.; Abdalla, Mohamed M.; Mayhoub, Abdelrahman S.
- Abstract
The usefulness of non-steroidal anti-inflammatory drugs (NSAIDs) is hampered by their gastrointestinal side effects. Non-selective cyclooxygenases inhibitors interfere with both COX-1 and COX-2 isozymes. Since COX-1 mediates cytoprotection of gastric mucosa, its inhibition leads to the undesirable side effects. On the other hand, COX-2 is undetectable in normal tissues and selectively induced by inflammatory stimuli. Therefore, it is strongly believed that the therapeutic benefits derive from inhibition of COX-2 only. The presence of a strong connection between reported COX-2 inhibitors and cardiac toxicity encourages medicinal chemists to explore new scaffolds. In the present study, we introduced imidazopyrazolopyridines as new potent and selective COX-2 inhibitors that lack the standard pharmacophoric binding features to hERG. Starting from our lead compound 5a, structure-based drug-design was conducted and more potent analogues were obtained with high COX-2 selectivity and almost full edema protection, in carrageenan-induced edema assay, in case of compound 5e. Increased bulkiness around imidazopyrazolopyridines by adding a substituted phenyl ring(s) afforded less active compounds.
- Subjects
IMIDAZOLES; ISOENZYMES; CYCLOOXYGENASES; GASTRIC mucosa; CYTOPROTECTION
- Publication
Molecules, 2015, Vol 20, Issue 8, p15287
- ISSN
1420-3049
- Publication type
Article
- DOI
10.3390/molecules200815287