A new class of acyclic 2-alkyl-1,1,2-triaryl (Z)-olefins as selective cyclooxygenase-2 inhibitors.
A new class of acyclic (Z)-2-alkyl-1,2-diphenyl-1-(4-methanesulfonylphenyl)ethenes (7) was designed for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1 and COX-2 isozyme inhibition structure-activity studies identified (Z)-1,2-diphenyl-1-(4-methanesulfonylphenyl)oct-1-ene (7d) as a potent COX-2 inhibitor (IC(50) = 0.42 microM) with a high COX-2 selectivity index (SI > 234). In a carrageenan-induced rat paw edema assay, (Z)-7d exhibited excellent antiinflammatory activity (ID(50) = 1.1 mg/kg). The molecular modeling and structure-activity data acquired indicate that (Z)-olefins having cis C-1 4-methanesulfonylphenyl and C-2 unsubstituted phenyl (or 4-acetoxyphenyl) substituents in conjunction with a C-1 phenyl ring and a C-2 alkyl substituent of appropriate length constitute a suitable template for the design of a novel class of acyclic (Z)-2-alkyl-1,1,2-triaryleth-1-ene COX-2 inhibitors.
Uddin
Md Jashim
MJ
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2N8.
Praveen Rao
P N
PN
McDonald
Robert
R
Knaus
Edward E
EE
D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001555:Benzene Derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051546:Cyclooxygenase 2; D005030:Ethylenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D011451:Prostaglandin-Endoperoxide Synthases; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001555:Benzene Derivatives; D005030:Ethylenes; D007527:Isoenzymes; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases