Synthesis and cyclooxygenase inhibitory activities of linear 1-(methanesulfonylphenyl or benzenesulfonamido)-2-(pyridyl)acetylene regioisomers

Abstract

A group of 1-(aminosulfonylphenyl and methylsulfonylphenyl)-2-(pyridyl)acetylene regioisomers were designed such that a COX-2 SO 2NH 2 pharmacophore was located at the para-position of the phenyl ring, or a SO 2Me pharmacophore was placed at the ortho-, meta- or para-position of the phenyl ring, on an acetylene template (scaffold). The point of attachment of the pyridyl ring to the acetylene linker was simultaneously varied (2-pyridyl, 3-pyridyl, 4-pyridyl, 3-methyl-2-pyridyl) to determine the combined effects of positional, steric, and electronic substituent properties upon COX-1 and COX-2 inhibitory potency and COX isozyme selectivity. These target linear 1-(phenyl)-2-(pyridyl)acetylenes were synthesized via a palladium-catalyzed Sonogashira cross-coupling reaction. Structure–activity relationship (SAR) data (IC 50 values) acquired by determination of the in vitro ability of the title compounds to inhibit the COX-1 and COX-2 isozymes showed that the position of the COX-2 SO 2NH 2 or SO 2Me pharmacophore on the phenyl ring, and the point of attachment of the pyridyl ring to the acetylene linker, were either individual, or collective, determinants of COX-2 inhibitory potency and selectivity. A number of compounds discovered in this study, particularly 1-(4-aminosulfonylphenyl)-2-(3-methyl-2-pyridyl)acetylene ( 22), 1-(3-methanesulfonylphenyl)-2-(2-pyridyl)acetylene ( 27), 1-(3-methanesulfonylphenyl)-2-(4-pyridyl)acetylene ( 29), 1-(4-methanesulfonylphenyl)-2-(2-pyridyl)acetylene ( 30), and 1-(4-methanesulfonylphenyl)-2-(3-pyridyl)acetylene ( 31), exhibit potent (IC 50 = 0.04–0.33 μM range) and selective (SI = 18 to >312 range) COX-2 inhibitory activities, that compare favorably with the reference drug celecoxib (COX-2 IC 50 = 0.07 μM; COX-2 SI = 473). The sulfonamide ( 22), and methylsulfonyl ( 27 and 31), compounds exhibited anti-inflammatory activities (ID 50 = 59.9–76.6 mg/kg range) that were intermediate in potency between the reference drugs aspirin (ID 50 = 128.7 mg/kg) and celecoxib (ID 50 = 10.8 mg/kg).