Synthesis and biological evaluation of substituted imidazoquinoline derivatives as mPGES-1 inhibitors.

Abstract We have previously reported 7-bromo-2-(2-chrolophenyl)-imidazoquinolin-4(5 H )-one ( 1 ) as a novel potent mPGES-1 inhibitor. To clarify the essential functional groups of 1 for inhibition of mPGES-1, we investigated this compound structure–activity relationship following substitution at the C (4)-position and N-alkylation at the N (1)-, the N (3)-, and the N (5)-positions of 1 . To prepare the target compounds, we established a good methodology for selective N-alkylation of the imidazoquinolin-4-one, that is, selective alkylation of 1 at the N (3)- and N (5)-positions was achieved by use of an appropriate base and introduction of a protecting group at the nitrogen atom in the imidazole part, respectively. Replacement of the C (4)-oxo group with nitrogen- or sulfur- linked substituents gave decreased inhibitory activity for mPGES-1, and introduction of alkyl groups on the nitrogen atom at the N (1)-, the N (3)-, and the N (5)-positions resulted in even larger loss of inhibitory activity. These results revealed that the C( 4)-oxo group, and the hydrogen atoms at the N (5)-position and the imidazole part were the best substituents.