title: Design, synthesis, and pharmacological evaluation of pyridinic analogues of nimesulide as cyclooxygenase-2 selective inhibitors.
abstract: In this study, we report the synthesis and pharmacological evaluation of original pyridinic sulfonamides related to nimesulide, a cyclooxygenase-2 (COX-2) preferential inhibitor widely used as an anti-inflammatory agent. These original pyridinic derivatives were synthesized in three steps starting from the condensation of 3-bromo-4-nitropyridine N-oxide with appropriately substituted phenols, thiophenols, or anilines followed by a reduction of the nitro moiety into the corresponding aminopyridine, which was finally condensed with alkane- or trifluoromethanesulfonyl chloride to obtain the corresponding sulfonamides. The pK(a) determinations demonstrated that the major ionic form present in solution at physiological pH depends on the nature of the sulfonamide moiety subsituent. Indeed, alkanesulfonamides were mainly present as zwitterionic molecules while trifluoromethanesulfonamides, more acidic derivatives, were mainly present as anionic molecules. The in vitro pharmacological evaluation of the synthesized compounds against COX-1 and COX-2 was performed in a human whole blood model. Results obtained demonstrated that most of alkanesulfonamide derivatives displayed a COX-2 preferential inhibition with selectivity ratio values (IC(50)(COX-1)/IC(50)(COX-2)) up to 7.92 (celecoxib displaying a ratio value of 7.46 in the same test). On the other hand, trifluoromethanesulfonamide derivatives displayed weaker selectivity ratios although they exhibited IC(50) values against COX-2 up to 0.09 microM (celecoxib IC(50) against COX-2: 0.35 microM). Finally, in vivo evaluation of selected compounds showed that they exhibited anti-inflammatory properties similar to that of nimesulide when tested in a carrageenan-induced rat paw oedema model.
authors.affiliation: Natural and Synthetic Drugs Research Centre, Laboratory of Medicinal Chemistry, Université de Liège, 1, Avenue de l'Hôpital, B36, B-4000 Liège, Belgium. f.julemont@ulg.ac.be
authors.forename: Fabien
authors.initials: F
authors.lastname: Julémont
authors.forename: Xavier
authors.initials: X
authors.lastname: de Leval
authors.forename: Catherine
authors.initials: C
authors.lastname: Michaux
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Renard
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Winum
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Montero
authors.forename: Jacques
authors.initials: J
authors.lastname: Damas
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Dogné
authors.forename: Bernard
authors.initials: B
authors.lastname: Pirotte
mesh_terms: D018360:Crystallography, X-Ray; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000737:chemistry; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D011725:Pyridines; D013449:Sulfonamides; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C012655:nimesulide