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.
Highlights
Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used for the treatment of inflammation, pain, and fever
When aminopyrazolopyridines 1 were allowed to react with a variety of hydrazonyl halides 2 in basic medium, a removal of hydrogen halide followed by cyclization through water loss led, to the imidazopyrazolopyridines 5a–l (Scheme 1)
Cyclooxygenase Inhibition Activity: all synthesized compounds were subjected to colorimetric screening assay utilizing the peroxidase component of cyclooxygenases (COX-1 and COX-2)
Summary
Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used for the treatment of inflammation, pain, and fever. From mechanistic point of view, NSAIDs exert their pharmacological action via inhibition of cyclooxygenase (COX) that catalyzes the conversion of arachidonic acid to the prostaglandins (PGs) [1]. PGs are hormone-like bio-substances that mediate different signaling pathways in many physiological and pathological processes. COX-1 is constitutively normally expressed in most tissues, and PGs controlled by COX-1 mediate cytoprotection of gastric mucosa and platelet aggregations in addition to some other physiological processes. COX-2 is undetectable in normal tissues and selectively induced locally by inflammatory stimuli; i.e., pro-inflammatory cytokines, leading to elevating PG levels at the site of inflammation [2,3]. The therapeutic benefits derives from inhibition of the inducible isoform; i.e., COX-2, at the site of inflammation [1]
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