N-(3-Arylaminopyridin-4-yl)alkanesulfonamides as pyridine analogs of nimesulide: cyclooxygenases inhibition, anti-inflammatory studies and insight on metabolism.
Nimesulide, a COX-2 preferential inhibitor with a favorable gastric and cardiovascular safety profile, was responsible for some cases of acute liver failure attributed to the nitrobenzene ring. A series of analogs of nimesulide resulting from isosteric replacement of the nitrobenzene ring by the pyridine nucleus, was synthesized and their ability to inhibit both cyclooxygenases (COXs) isoforms was evaluated in vitro using a human whole blood model. Compounds 19c, 23b and 23c displayed an important inhibitory activity associated to a COX-2/COX-1 selectivity ratio similar to or higher than that of celecoxib. The anti-inflammatory activity and the ability of several compounds to decrease leukocyte infiltration were further evaluated in vivo in a model of a λ carrageenan-induced pleurisy. Plasma assays were performed on blood samples collected from rats and allowed us to identify the 4-position of the phenyl ring as a major metabolism site explaining the occasionally observed lack of correlation between in vitro and in vivo results.
Center for Interdisciplinary Research on Medicines (CIRM), Laboratory of Medicinal Chemistry, University of Liège, Av. de l'Hôpital 1, B-4000 Liège, Belgium.
Jean-François
JF
Renard
Center for Interdisciplinary Research on Medicines (CIRM), Laboratory of Analytical Chemistry, University of Liège, Av. de l'Hôpital 1, B-4000 Liège, Belgium.
Frédéric
F
Lecomte
Center for Interdisciplinary Research on Medicines (CIRM), Laboratory of Analytical Chemistry, University of Liège, Av. de l'Hôpital 1, B-4000 Liège, Belgium.
Philippe
P
Hubert
Center for Interdisciplinary Research on Medicines (CIRM), Laboratory of Medicinal Chemistry, University of Liège, Av. de l'Hôpital 1, B-4000 Liège, Belgium.
Xavier
X
de Leval
Center for Interdisciplinary Research on Medicines (CIRM), Laboratory of Medicinal Chemistry, University of Liège, Av. de l'Hôpital 1, B-4000 Liège, Belgium. Electronic address: B.Pirotte@ulg.ac.be.
Bernard
B
Pirotte
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D011725:Pyridines / Q000737:chemistry*; D051381:Rats; D013449:Sulfonamides / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*
D000893:Anti-Inflammatory Agents; D016861:Cyclooxygenase Inhibitors; D011725:Pyridines; D013449:Sulfonamides; C023666:pyridine; C012655:nimesulide
COXs inhibitors; Nimesulide; Nonsteroidal anti-inflammatory drugs; λ carrageenan-induced pleurisy