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.

中文翻译：

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多取代的嘧啶类化合物作为mPGES-1抑制剂：在卡拉胶诱导的大鼠爪水肿中发现具有强抗炎作用的强效PGE2抑制剂。

我们报道了对多取代嘧啶进行的广泛的构效关系优化，从而发现了5-丁基-4-（4-苄氧基苯基）-6-苯基嘧啶-2-胺及其二氟类似物。这些化合物是PGE ₂产生的亚微摩尔抑制剂（IC ₅₀低至12 nM）。为了确定抗炎嘧啶的分子靶标，我们进行了广泛的研究，包括酶法测定，同源性建模和对接。二氟类似物同时抑制花生四烯酸级联的两个关键酶，即mPGES-1和COX-2，其中mPGES-1的抑制是主要的作用机理。研究的其他嘧啶类是有效的mPGES-1抑制剂，没有观察到对COX-1 / 2酶的抑​​制作用。此外，在急性炎症模型中，两种最有效的化合物在体内被证明是有效的，将角叉菜胶诱导的大鼠爪水肿抑制了36％和46％。这项研究的有希望的结果值得对所选的抗炎候选药物进行进一步的临床前评估。