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.

Research developments in the syntheses, anti-inflammatory activities and structure–activity relationships of pyrimidines

“…29). 105 Synthesis and anti-inammatory activities of several new pyrimidin-2-thione derivatives have been reported. COXinhibitory effects of the synthesized compounds were measured by Cayman colorimetric COX (ovine) inhibitor screening assay kit.…”

Polysubstituted Pyrimidines as Potent Inhibitors of Prostaglandin E2 Production: Increasing Aqueous Solubility

“…Since the prepared derivatives were more soluble compared to compound 1 (see water solubility determination below), we decided to expand this approach and we designed novel compound 17 (Figure 2) as a combination of soluble derivative 14 and previously reported 13 potent inhibitor of PGE 2 production, compound 16 (IC 50 = 31 nM, 99.7 % inhibition of PGE 2 production), which was approx. 150-fold more potent compared to compound 1 (IC 50 = 4.83 μM, 87.7 % inhibition of PGE 2 production).…”

“…[10,11] Later, series of 2-amino-4,6-diarylpyrimidines were synthesized and studied as potent inhibitors of PGE 2 production. [12,13] Moreover, the compounds exhibited strong anti-inflammatory in vivo effects in the rat model of acute inflammation. [13] Among the polysubstituted pyrimidines studied, 5-butyl-4-(4-methoxyphenyl)-6-phenylpyrimidin-2-amine (1, Figure 1) was identified as a potential lead structure with anti-inflammatory properties, [12,14] but a significant drawback of this compound was its low water solubility.…”

“…The compounds were shown to be inhibitors of immune‐activated nitric oxide (NO) production [8,9] or dual inhibitors of NO and prostaglandin E 2 (PGE 2 ) production [10,11] . Later, series of 2‐amino‐4,6‐diarylpyrimidines were synthesized and studied as potent inhibitors of PGE 2 production [12,13] . Moreover, the compounds exhibited strong anti‐inflammatory in vivo effects in the rat model of acute inflammation [13] …”

“…Later, series of 2‐amino‐4,6‐diarylpyrimidines were synthesized and studied as potent inhibitors of PGE 2 production [12,13] . Moreover, the compounds exhibited strong anti‐inflammatory in vivo effects in the rat model of acute inflammation [13] …”