Polysubstituted Pyrimidines as mPGES-1 Inhibitors: Discovery of Potent Inhibitors of PGE 2 Production with Strong Anti-inflammatory Effects in Carrageenan-Induced Rat Paw Edema.

Autor: Kalčic F; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo nám. 2, 166 10, Prague 6, Czech Republic.; Department of Organic Chemistry, Faculty of Science, Charles University, Hlavova 8, 128 43, Prague 2, Czech Republic., Kolman V; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo nám. 2, 166 10, Prague 6, Czech Republic., Ajani H; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo nám. 2, 166 10, Prague 6, Czech Republic., Zídek Z; Institute of Experimental Medicine of the Czech Academy of Sciences, Vídeňská 1083, 142 20, Prague 4, Czech Republic., Janeba Z; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo nám. 2, 166 10, Prague 6, Czech Republic.
Jazyk: angličtina
Zdroj: ChemMedChem [ChemMedChem] 2020 Aug 05; Vol. 15 (15), pp. 1398-1407. Date of Electronic Publication: 2020 Jun 04.
DOI: 10.1002/cmdc.202000258
Abstrakt: 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 PGE 2 production (IC 50 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.
(© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)
Databáze: MEDLINE
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