A group of 4-carboxyl quinoline derivatives possessing a methylsulfonyl COX-2 pharmacophore at the para position of the C-2 phenyl ring were designed and synthesized as selective COX-2 inhibitors. In vitro COX-1/COX-2 structure-activity relationships were determined by varying the substituents on the C-7 and C-8 quinoline ring. Among the 4-carboxyl quinolines, 7,8,9,10-tetrahydro-2-(4-(methyl sulfonyl)phenyl)benzo[h]quinoline-4-carboxylic acid (9e) was identified as potent and high selective COX-2 inhibitor (COX-2 IC(50)=0.043microM; selectivity index>513) that was more potent than the reference drug celecoxib (COX-2 IC(50)=0.060microM; SI=405). A molecular modeling study where 9e was docked in the binding site of COX-2 showed that the p-MeSO(2) substituent on the C-2 phenyl ring is oriented in the vicinity of the COX-2 secondary pocket (Arg513, Phe518 and Val523) and the carboxyl group can interact with Arg120. The structure activity data acquired indicate that the presence of lipophilic substituents on the C-7 and C-8 quinoline ring is important for COX-2 inhibitory activity.