Pyridine and Fused Pyridine Derivatives as Selective COX-2 Inhibitors: A Comprehensive Review of Synthetic Pathways, Anti-Inflammatory, and Antinociceptive Activities.

Selective cyclooxygenase-2 inhibitors (COXIBs) are preferred over traditional nonsteroidal anti-inflammatory drugs (NSAIDs) owing to their improved gastrointestinal and renal safety profile. Pyridine is one of the most important nitrogen-containing heterocyclic scaffolds, and it is present in the structures of more than 7000 marketed drugs and biologically active compounds. Among these are anti-inflammatory agents, including the selective cyclooxygenase-2 (COX-2) inhibitors niflumic acid and etoricoxib. This review highlights the synthetic approaches to pyridine and fused pyridine derivatives, covering 42 published studies on pyridine synthesis, and critically evaluates 40 published studies on pyridine-containing scaffolds exhibiting COX-2 inhibitory activity. Several pyridine derivatives demonstrated potent COX-2 inhibitory activity, with reported IC50 values ranging from the nanomolar to micromolar level. Analysis of these studies revealed that 17 of the 40 studies reported compounds that exhibited superior COX-2 inhibitory activity than the reference drugs evaluated under the same experimental conditions. Among these 17 studies, 6 involved fused pyridine scaffolds. These findings support the pyridine scaffold as a promising platform for the development of selective COX-2 inhibitors. Therefore, this review provides a valuable resource for guiding the rational design and development of novel selective COX-2 inhibitors.