Influence of the C-5 substitution in polysubstituted pyrimidines on inhibition of prostaglandin E2 production

• Published in: European journal of medicinal chemistry 2018-08, Vol.156, p.295-301
• Main Authors: Kolman, Viktor, Kalčic, Filip, Jansa, Petr, Zídek, Zdeněk, Janeba, Zlatko
• Format: Article
• Language: English
• Subjects: Inhibitor; Prostaglandin E2; Pyrimidines; Suzuki-Miyaura reaction
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.07.010

As a part of a broader structure-activity relationship study of substituted 2-aminopyrimidines, the influence of the C-5 substitution on inhibition of prostaglandin E2 (PGE2) production was studied. Thirty compounds were prepared starting from the corresponding 2-amino-4,6-dichloropyrimidines using Suzuki cross-coupling. It was shown previously that 2-amino-4,6-dichloropyrimidines with smaller C-5 substituent (hydrogen and methyl) were devoid of significant activity, while 5-butyl derivatives exhibited prominent potency. In this study, on the other hand, both monoaryl- and bisarylpyrimidines were potent inhibitors of PGE2 production regardless the length of the C-5 substituent (hydrogen, methyl, n-butyl). Moreover, the shorter the C-5 substituent the higher potency to inhibit PGE2 production was observed. 2-Amino-4,6-diphenylpyrimidine was the best inhibitor of PGE2 production with IC50 = 3 nM and no cytotoxicity. The most potent inhibitors deserve further preclinical evaluation as potential anti-inflammatory agents. [Display omitted] •Synthesis of polysubstituted pyrimidines using Suzuki-Miyaura cross-coupling reaction.•Potent inhibitors of prostaglandin E2 production.•No cytotoxicity observed at the concentrations tested.•Potential anti-inflammatory agents.