Pyridine analogues of nimesulide: design, synthesis, and in vitro and in vivo pharmacological evaluation as promising cyclooxygenase 1 and 2 inhibitors.
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 lambda carrageenan-induced pleurisy in rats. Some of the selected compounds displayed similar or improved anti-inflammatory properties when compared to nimesulide and celecoxib.
Drug Research Center (CIRM), Laboratory of Medicinal Chemistry, University of Liege, Liege, Belgium. jf.renard@ulg.ac.be
Jean-François
JF
Renard
Deniz
D
Arslan
Nancy
N
Garbacki
Bernard
B
Pirotte
Xavier
X
de Leval
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000068579:Celecoxib; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis*; D015195:Drug Design; D006801:Humans; D010998:Pleurisy / Q000188:drug therapy*; D011720:Pyrazoles; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D013449:Sulfonamides; D000068579:Celecoxib; C012655:nimesulide