Pyridine Analogues of Nimesulide: Design, Synthesis, and in Vitro and in Vivo Pharmacological Evaluation as Promising Cyclooxygenase 1 and 2 Inhibitors

• Published in: Journal of medicinal chemistry Vol. 52; no. 19; pp. 5864 - 5871
• Main Authors: Renard, Jean-François, Arslan, Deniz, Garbacki, Nancy, Pirotte, Bernard, de Leval, Xavier
• Format: Journal Article Web Resource
• Language: English
• Published: Columbus, OH American Chemical Society 08-10-2009
• Subjects: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Celecoxib; Cyclooxygenase 2 Inhibitors - chemical synthesis; Cyclooxygenase Inhibitors - chemical synthesis; Drug Design; Human health sciences; Humans; Medical sciences; Neuropharmacology; Pharmacie, pharmacologie & toxicologie; Pharmacology. Drug treatments; Pharmacy, pharmacology & toxicology; Pleurisy - drug therapy; Pyrazoles; Pyridines - chemical synthesis; Pyridines - pharmacology; Pyridines - therapeutic use; Rats; Sciences de la santé humaine; Sulfonamides - chemical synthesis; Sulfonamides - pharmacology; Sulfonamides - therapeutic use; Prostaglandin-endoperoxide synthase; Rat; Cyclooxygenase 2; Cyclooxygenase 1; Cyclooxygenase 2 inhibitor; Pyridine derivatives; Structure activity relation; Chlorine Organic compounds; Bromine Organic compounds; Nimesulide; Chemical synthesis; Sulfonamide; Enzyme; Rodentia; Enzyme inhibitor; In vitro; Cyclooxygenase 1 inhibitor; Non steroidal antiinflammatory agent; In vivo; Vertebrata; Mammalia; Analgesic; Animal; Antipyretic; Oxidoreductases
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/jm900702b

Nonsteroidal anti-inflammatory drugs (NSAIDs) represent one of the most prescribed medications, although the chronic use of such pharmacological agents is commonly associated with numerous side effects. The demonstration that the use of COX-2 selective or preferential inhibitors is associated with a better tolerability opened new horizons in the search of safer drugs for the management of inflammation. In the present study, we report the synthesis and the pharmacological evaluation of pyridine analogues of nimesulide, a COX-2 preferential inhibitor. The cyclooxygenases (COXs) inhibitory activities were evaluated in vitro using a human whole blood model. According to the in vitro results, a selection of compounds exhibiting moderate to high COX-2/COX-1 selectivity ratio (from weak COX-2 preferential inhibitors to compounds displaying a celecoxib-like selectivity profile) were further evaluated in vivo in a model of λ carrageenan-induced pleurisy in rats. Some of the selected compounds displayed similar or improved anti-inflammatory properties when compared to nimesulide and celecoxib.