title: Design and Synthesis of Imidazopyrazolopyridines as Novel Selective COX-2 Inhibitors.
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.
authors: Chemistry Department, Faculty of Science, Fayoum University, El-Fayoum 63551, Egypt. mgb00@fayoum.edu.eg.
authors: Mohamed G
authors: MG
authors: Badrey
authors: Department of Chemistry, Faculty of Science, Bani Suef University, Bani Suef 62111, Egypt. dr_hassan1971@yahoo.com.
authors: Hassan M
authors: HM
authors: Abdel-Aziz
authors: Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt. s.m.gomha@hotmail.com.
authors: Sobhi M
authors: SM
authors: Gomha
authors: Research Unit, Saco Pharm. Co., 6th of October City 68330, Egypt. dr_mohamed211@yahoo.com.
authors: Mohamed M
authors: MM
authors: Abdalla
authors: Department of Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt. amayhoub@hotmail.com.
authors: Abdelrahman S
authors: AS
authors: Mayhoub
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D015195:Drug Design; D004487:Edema / Q000188:drug therapy; D006801:Humans; D007093:Imidazoles / Q000737:chemistry*; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry*; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry*; D051381:Rats; D011994:Recombinant Proteins
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D007093:Imidazoles; D011720:Pyrazoles; D011725:Pyridines; D011994:Recombinant Proteins; C118531:pyrazolopyridine; C029899:imidazole
keywords: aminopyrazolopyridine; anti-inflammatory; cyclooxygenase; hydrazonyl halides; selective inhibitors