Mechanisms of Inhibitory Effects of Polysubstituted Pyrimidines on Prostaglandin E₂ Production ^†

The pyrimidine heterocycle represents an elemental structural motif of numerous drugs. We have synthesized a large series of original derivatives possessing different substituents at C-2, C-4, C-5, and C-6 positions of the pyrimidine ring. The vast majority of prepared pyrimidines inhibit prostaglandin E₂ (PGE₂) production as revealed in vitro in the lipopolysaccharide (LPS)-stimulated mouse macrophages [1,2]. A number of them are effective at sub-micromolar concentration. The compounds are devoid of cytotoxic effects. They do not inhibit activities of phospholipase A2 (sPLA2), cyclooxygenases COX-1 and COX-2, and important enzymes in the PGE₂ biosynthesis pathway. A plausible explanation for the mechanism of PGE₂-inhibitory effects of pyrimidines is provided by findings showing substantial inhibition of activity of the terminal enzyme in PGE₂ formation, i.e., microsomal prostaglandin E₂ synthase-1 (mPGES-1). The IC₅₀s characterizing the potential of compounds to reduce mPGES-1 activity on one site and LPS-induced PGE₂ production on the other one are statistically significantly correlated.

Pyrimidine derivatives exhibit anti-inflammatory activity in vivo, as demonstrated by the significant reduction of carrageenan-induced paw oedema in rats. The findings suggest that pyrimidine inhibitors of mPGES-1 activity and consequent PGE₂ production may be considered as promising candidates for further preclinical research and development of novel non-steroidal anti-inflammatory drugs.