A group of (E)-and (Z)-1,2,3-triaryl-2-propen-1-one derivatives possessing a methylsulfonyl COX-2 pharmacophore at the para position of the C-1 phenyl ring were synthesized and evaluated as selective COX-2 inhibitors. In vitro COX-1/COX-2 structure-activity relationships were determined by varying the substituents on the C-3 propenone moiety. Among the 1,2,3-triaryl-2-propen-1-ones, (Z)-1-(4-(methylsulfonyl)phenyl)-2,3-diphenylprop-2-en-1-one (3b) showed the most potency and selectivity on COX-2 inhibition (COX-2 IC(50) = 0.07 microM; selectivity index = 201). The Z-propenones were also found to be more potent and selective than their E-isomers for COX-2 inhibitory activity. The structure-activity data acquired indicate that the geometry of propenone and also the type of substituents on the C-3 propenone are important for COX-2 inhibitory activity.