Novel synthesis of 3,4-diarylisoxazole analogues of valdecoxib: reversal cyclooxygenase-2 selectivity by sulfonamide group removal.
3,4-Diarylisoxazole analogues of valdecoxib [4-(5-methyl-3-phenylisoxazol-4-yl)-benzensulfonamide], a selective cyclooxygenase-2 (COX-2) inhibitor, were synthesized by 1,3-dipolar cycloaddition of arylnitrile oxides to the enolate ion of phenylacetone regioselectively prepared in situ with lithium diisopropylamide at 0 degrees C. The corresponding 3-aryl-5-methyl-4-phenylisoxazoles were easily generated by a dehydration/aromatization reaction under basic conditions of 3-aryl-5-hydroxy-5-methyl-4-phenyl-2-isoxazolines and further transformed into their benzenesulfonamide derivatives. The biochemical COX-1/COX-2 selectivity was evaluated in vitro by using the human whole blood assays of COX isozyme activity. Three compounds not bearing the sulfonamide group present in valdecoxib were selective COX-1 inhibitors.
Di Nunno
Leonardo
L
Dipartimento Farmaco-Chimico, Università di Bari, Via Orabona no. 4, 70125 Bari, Italy.
Vitale
Paola
P
Scilimati
Antonio
A
Tacconelli
Stefania
S
Patrignani
Paola
P
D000328:Adult; D001671:Biochemistry / Q000379:methods; D001769:Blood / Q000187:drug effects / Q000378:metabolism; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007555:Isoxazoles / Q000737:chemistry* / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008565:Membrane Proteins; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology; D013929:Thromboxane B2 / Q000378:metabolism; D000096926:Benzenesulfonamides
D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D015232:Dinoprostone; D007527:Isoenzymes; D007555:Isoxazoles; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases; D013449:Sulfonamides; D013929:Thromboxane B2; C406224:valdecoxib; D000096926:Benzenesulfonamides; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human