Design and Synthesis of Imidazopyrazolopyridines as Novel Selective COX-2 Inhibitors

Molecules

Mohamed G. Badrey¹  Hassan M. Abdel-Aziz²  Sobhi M. Gomha⁴  Mohamed M. Abdalla⁵  Abdelrahman S. Mayhoub³ 

[1] Chemistry Department, Faculty of Science, Fayoum University, El-Fayoum 63551, Egypt; E-Mail:;Department of Chemistry, Faculty of Science, Bani Suef University, Bani Suef 62111, Egypt; E-Mail:;Department of Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt; E-Mail:;Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt;Research Unit, Saco Pharm. Co., 6th of October City 68330, Egypt; E-Mail:

关键词: aminopyrazolopyridine;    anti-inflammatory;    cyclooxygenase;    hydrazonyl halides;    selective inhibitors;   

DOI  :  10.3390/molecules200815287

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2015 by the authors; licensee MDPI, Basel, Switzerland.