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

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...

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Bibliographic Details
Published in:ChemMedChem 2020-08, Vol.15 (15), p.1398-1407
Main Authors: Kalčic, Filip, Kolman, Viktor, Ajani, Haresh, Zídek, Zdeněk, Janeba, Zlatko
Format: Article
Language:English
Subjects:
anti-inflammatory
Arachidonic acid
Carrageenan
Edema
Enzymes
Homology
Inflammation
Inhibitors
mPGES-1
Optimization
Prostaglandin E2
Pyrimidines
Suzuki Miyaura reaction
Target recognition
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Summary: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. Paw health: Anti‐inflammatory drugs are among the most used therapeutic agents, but both traditional NSAIDs and coxibs suffer from serious side effects. mPGES‐1 inhibitors may be good candidates for anti‐inflammatory drugs with a novel mechanism of action. We have designed and synthesized potent mPGES‐1 inhibitors based on polysubstituted pyrimidines, which showed strong anti‐inflammatory effects in vivo.
ISSN:1860-7179
1860-7187
DOI:10.1002/cmdc.202000258