Synthesis and cyclooxygenase inhibitory activities of linear 1-(methanesulfonylphenyl or benzenesulfonamido)-2-(pyridyl)acetylene regioisomers.
A group of 1-(aminosulfonylphenyl and methylsulfonylphenyl)-2-(pyridyl)acetylene regioisomers were designed such that a COX-2 SO2NH2 pharmacophore was located at the para-position of the phenyl ring, or a SO2Me 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 (IC50 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 SO2NH2 or SO2Me 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 (IC50 = 0.04-0.33 microM range) and selective (SI = 18 to >312 range) COX-2 inhibitory activities, that compare favorably with the reference drug celecoxib (COX-2 IC50 = 0.07 microM; COX-2 SI = 473). The sulfonamide (22), and methylsulfonyl (27 and 31), compounds exhibited anti-inflammatory activities (ID50 = 59.9-76.6 mg/kg range) that were intermediate in potency between the reference drugs aspirin (ID50 = 128.7 mg/kg) and celecoxib (ID50 = 10.8 mg/kg).
Chowdhury
Morshed Alam
MA
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alta., Canada T6G 2N8.
Dong
Ying
Y
Chen
Qiao-Hong
QH
Abdellatif
Khaled R A
KR
Knaus
Edward E
EE
D000480:Alkynes / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry* / Q000494:pharmacology; D052246:Cyclooxygenase 2 Inhibitors / Q000737:chemistry / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D013329:Structure-Activity Relationship
D000480:Alkynes; D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors