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Design and Synthesis of Imidazopyrazolopyridines as Novel Selective COX-2 Inhibitors
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 s...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6332013/ https://www.ncbi.nlm.nih.gov/pubmed/26307959 http://dx.doi.org/10.3390/molecules200815287 |
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author | Badrey, Mohamed G. Abdel-Aziz, Hassan M. Gomha, Sobhi M. Abdalla, Mohamed M. Mayhoub, Abdelrahman S. |
author_facet | Badrey, Mohamed G. Abdel-Aziz, Hassan M. Gomha, Sobhi M. Abdalla, Mohamed M. Mayhoub, Abdelrahman S. |
author_sort | Badrey, Mohamed G. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6332013 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-63320132019-01-24 Design and Synthesis of Imidazopyrazolopyridines as Novel Selective COX-2 Inhibitors Badrey, Mohamed G. Abdel-Aziz, Hassan M. Gomha, Sobhi M. Abdalla, Mohamed M. Mayhoub, Abdelrahman S. Molecules Article 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. MDPI 2015-08-21 /pmc/articles/PMC6332013/ /pubmed/26307959 http://dx.doi.org/10.3390/molecules200815287 Text en © 2015 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Badrey, Mohamed G. Abdel-Aziz, Hassan M. Gomha, Sobhi M. Abdalla, Mohamed M. Mayhoub, Abdelrahman S. Design and Synthesis of Imidazopyrazolopyridines as Novel Selective COX-2 Inhibitors |
title | Design and Synthesis of Imidazopyrazolopyridines as Novel Selective COX-2 Inhibitors |
title_full | Design and Synthesis of Imidazopyrazolopyridines as Novel Selective COX-2 Inhibitors |
title_fullStr | Design and Synthesis of Imidazopyrazolopyridines as Novel Selective COX-2 Inhibitors |
title_full_unstemmed | Design and Synthesis of Imidazopyrazolopyridines as Novel Selective COX-2 Inhibitors |
title_short | Design and Synthesis of Imidazopyrazolopyridines as Novel Selective COX-2 Inhibitors |
title_sort | design and synthesis of imidazopyrazolopyridines as novel selective cox-2 inhibitors |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6332013/ https://www.ncbi.nlm.nih.gov/pubmed/26307959 http://dx.doi.org/10.3390/molecules200815287 |
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