Synthesis and biological evaluation of methanesulfonamide analogues of rofecoxib: Replacement of methanesulfonyl by methanesulfonamido decreases cyclooxygenase-2 selectivity

• Published in: Bioorganic & medicinal chemistry 2007-01, Vol.15 (2), p.1056-1061
• Main Authors: Zarghi, Afshin, Praveen Rao, P.N., Knaus, Edward E.
• Format: Article
• Language: English
• Subjects: Cyclooxygenase 1 - metabolism; Cyclooxygenase 2 Inhibitors - chemical synthesis; Cyclooxygenase 2 Inhibitors - pharmacology; Cyclooxygenase inhibition; Cyclooxygenase Inhibitors - chemical synthesis; Cyclooxygenase Inhibitors - pharmacology; Indicators and Reagents; Lactones - chemical synthesis; Lactones - pharmacology; Magnetic Resonance Spectroscopy; Methanesulfonamido pharmacophore; Models, Molecular; Rofecoxib analogues; Spectrophotometry, Infrared; Spectroscopy, Fourier Transform Infrared; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - pharmacology; Sulfones - chemical synthesis; Sulfones - pharmacology
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2006.10.023

A new group of 3-(4-substituted-phenyl)-4-(4-methylsulfonamidophenyl)-2(5 H)furanones in which the methylsulfonyl (MeSO 2) COX-2 pharmacophore present in rofecoxib was replaced by a methanesulfonamido (MeSO 2NH) moiety, and where the substituent at the para-position of the C-3 phenyl ring was simultaneously varied (H, F, Cl, Br, Me, OMe), were evaluated to determine the combined effects of steric and electronic substituent properties upon COX-1 and COX-2 inhibitory potency and COX isozyme selectivity. Structure–activity relationship (SAR) studies showed that compounds having a neutral (H), or electronegative halogen (F, Cl, Br), substituent at the para-position of the C-3 phenyl ring inhibited both COX-1 and COX-2 with COX-2 selectivity indexes in the 3.1–39.4 range. In contrast, compounds having an electron-donating Me or OMe substituent were selective inhibitors of COX-2 (COX-1 IC 50 > 100 μM). These SAR data indicate the 3-aryl-4-(4-methylsulfonamidophenyl)-2(5 H)furanone scaffold provides a suitable template to design COX inhibitors with variable COX-2 selectivity indexes.