Novel Synthesis of 3,4-Diarylisoxazole Analogues of Valdecoxib:  Reversal Cyclooxygenase-2 Selectivity by Sulfonamide Group Removal

• Published in: Journal of medicinal chemistry Vol. 47; no. 20; pp. 4881 - 4890
• Main Authors: Di Nunno, Leonardo, Vitale, Paola, Scilimati, Antonio, Tacconelli, Stefania, Patrignani, Paola
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 23.09.2004; Amer Chemical Soc
• Subjects: Adult; Biochemistry - methods; Biological and medical sciences; Blood - drug effects; Blood - metabolism; Blood Platelets - drug effects; Blood Platelets - enzymology; Bones, joints and connective tissue. Antiinflammatory agents; Chemistry, Medicinal; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors - chemical synthesis; Cyclooxygenase Inhibitors - chemistry; Cyclooxygenase Inhibitors - pharmacology; Dinoprostone - metabolism; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical - methods; Female; Humans; Inhibitory Concentration 50; Isoenzymes - antagonists & inhibitors; Isoenzymes - metabolism; Isoxazoles - chemistry; Isoxazoles - pharmacology; Life Sciences & Biomedicine; Lipopolysaccharides - pharmacology; Medical sciences; Membrane Proteins; Monocytes - drug effects; Monocytes - enzymology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Prostaglandin-Endoperoxide Synthases - metabolism; Science & Technology; Structure-Activity Relationship; Sulfonamides - chemistry; Sulfonamides - pharmacology; Thromboxane B2 - metabolism; RHEUMATOID-ARTHRITIS; INHIBITION; LOW-DOSE ASPIRIN; CHLOROSULFURIC ACID; HEALTHY-SUBJECTS; ACUTE PAIN; BIOCHEMICAL SELECTIVITY; INTESTINAL TUMORIGENESIS; AROMATIC SULFONATION; THICK ASCENDING LIMB; Prostaglandin-endoperoxide synthase; Sulfonamide; Isoxazole derivatives; Enzyme; Cyclooxygenase 2; Enzyme inhibitor; Cyclooxygenase 2 inhibitor; Selectivity; Valdecoxib; In vitro; Dose activity relation; Structure activity relation; Benzenic compound; Oxidoreductases; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm040782x

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 °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.