Spectral and crystallographic study of pyridinic analogues of nimesulide: determination of the active form of methanesulfonamides as COX-2 selective inhibitors.
Compound 7, N-(3-phenoxy-4-pyridinyl)trifluoromethanesulfonamide, showed in vitro (whole blood assay) a strong inhibitory activity on the two cyclooxygenase (COX) enzymes (IC(50)(COX-1) = 2.2 microM and IC(50)(COX-2) = 0.4 microM), being more active but less COX-2-selective than nimesulide. Physicochemical studies and structural analyses indicated that the anionic sulfonamidate species seemed to be the active form of methanesulfonamides, which optimally interacted with the COX enzymes' active sites.
Julémont
Fabien
F
Natural and Synthetic Drugs Research Center, Department of Medicinal Chemistry, Université de Liège, 1, Avenue de l'Hôpital, Tour 4(+5) Sart-Tilman, Belgium. f.julemont@ulg.ac.be
de Leval
Xavier
X
Michaux
Catherine
C
Damas
Jacques
J
Charlier
Caroline
C
Durant
François
F
Pirotte
Bernard
B
Dogné
Jean-Michel
JM
D000631:Aminopyridines / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000838:Anions; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D004487:Edema / Q000188:drug therapy; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases; D051381:Rats; D017208:Rats, Wistar; D013055:Spectrophotometry, Infrared; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology
D000631:Aminopyridines; D000838:Anions; D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; C468797:N-(3-phenoxy-4-pyridinyl)trifluoromethanesulfonamide; D013449:Sulfonamides; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; C012655:nimesulide