Polysubstituted Pyrimidines as mPGES‐1 Inhibitors: Discovery of Potent Inhibitors of PGE2 Production with Strong Anti‐inflammatory Effects in Carrageenan‐Induced Rat Paw Edema

Abstract

We report an extensive structure-activity relationship optimization of polysubstituted pyrimidines that led to the discovery of 5-butyl-4-(4-benzyloxyphenyl)-6-phenylpyrimidin-2-amine, and its difluorinated analogue. These compounds are sub-micromolar inhibitors of PGE2 production (IC50 as low as 12 nM). In order to identify the molecular target of anti-inflammatory 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-1 and COX-2, with mPGES-1 inhibition being the principal mechanism of action. Other pyrimidines studied are potent mPGES-1 inhibitors with no observed inhibition of COX-1/2 enzymes. Moreover, the two most potent compounds proved to be significantly effective in vivo in a model of acute inflammation, suppressing carrageenan-induced rat paw edema by 36 and 46 %. The promising results of this study warrant further preclinical evaluation of selected anti-inflammatory candidates.