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These compounds are sub\u2010micromolar inhibitors of PGE<jats:sub>2<\/jats:sub> production (IC<jats:sub>50<\/jats:sub> as low as 12\u2005nM). In order to identify the molecular target of anti\u2010inflammatory pyrimidines, we performed extensive studies including enzymatic assays, homology modeling and docking. The difluorinated analogue simultaneously inhibits two key enzymes of the arachidonic acid cascade, namely mPGES\u20101 and COX\u20102, with mPGES\u20101 inhibition being the principal mechanism of action. Other pyrimidines studied are potent mPGES\u20101 inhibitors with no observed inhibition of COX\u20101\/2 enzymes. Moreover, the two most potent compounds proved to be significantly effective <jats:italic>in\u2005vivo<\/jats:italic> in a model of acute inflammation, suppressing carrageenan\u2010induced rat paw edema by 36 and 46\u2009%. 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