Novel 2-(4-methylsulfonylphenyl)pyrimidine derivatives as highly potent and specific COX-2 inhibitors

• Published in: Bioorganic & medicinal chemistry 2008-03, Vol.16 (5), p.2183-2199
• Main Authors: Orjales, Aurelio, Mosquera, Ramón, López, Beatriz, Olivera, Roberto, Labeaga, Luis, Núñez, M. Teresa
• Format: Article
• Language: English
• Subjects: 2-(4-Methylsulfonylphenyl)pyrimidines; 2-(4-Sulfamoylphenyl)pyrimidines; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; COX-2 inhibitors; Cyclooxygenase 2 Inhibitors - chemical synthesis; Cyclooxygenase 2 Inhibitors - chemistry; Cyclooxygenase 2 Inhibitors - pharmacology; Inhibitory Concentration 50; Medical sciences; Methylation; Molecular Structure; Pharmacology. Drug treatments; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Structure-Activity Relationship; Sulfur Compounds - chemical synthesis; Sulfur Compounds - chemistry; Sulfur Compounds - pharmacology
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2007.11.079

New series of pyrimidines I were synthesized and evaluated as cyclooxygenase-2 (COX-2) inhibitors. Compounds 8, 67, 69, 71, 82 and 83 were highly potent and specific COX-2 inhibitors (HWB COX-2 IC 50 = 2.4–0.3 nM and 80- to 780-fold more selective than rofecoxib). New series of 2-(4-methylsulfonylphenyl) and 2-(4-sulfamoylphenyl)pyrimidines were synthesized and evaluated for their ability to inhibit cyclooxygenase-2 (COX-2). COX-1 and COX-2 inhibitory activity of these compounds was determined using purified enzyme (PE) and human whole blood (HWB) assays. Extensive structure–activity relationship (SAR) work was carried out within these series, and a wide number of potent and specific COX-2 inhibitors were identified (HWB COX-2 IC 50 = 2.4–0.3 nM and 80- to 780-fold more selective than rofecoxib).