Novel 1,3,4-oxadiazole derivatives as highly potent microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitors

[Display omitted] •New 1,3,4-oxadiazole derivatives as potent mPGES-1 inhibitors are reported.•Compounds showed potent mPGES-1 inhibitory activity with IC50 of 5.6 – 82.3 nM.•TG554 selectively inhibits inflammatory PGE2 formation over all COX-derived prostanoids.•TG554 does not cause substrate shunting towards 5-LOX pathway. Selective inhibition of microsomal prostaglandin E2 synthase-1 (mPGES-1) is implicated as a new therapeutic modality for the development of new-generation anti-inflammatory drugs. Here, we present the discovery of new and potent inhibitors of human mPGES-1, i.e., compounds 13, 15–25, 29–30 with IC50 values in the range of 5.6–82.3 nM in a cell-free assay of prostaglandin (PG)E2 formation. We also demonstrate that 20 (TG554, IC50 = 5.6 nM) suppresses leukotriene (LT) biosynthesis at low µM concentrations, providing a benchmark compound that dually intervenes with inflammatory PGE2 and LT biosynthesis. Comprehensive lipid mediator (LM) metabololipidomics with activated human monocyte-derived macrophages showed that TG554 selectively inhibits inflammatory PGE2 formation over all cyclooxygenase (COX)-derived prostanoids, does not cause substrate shunting towards 5-lipoxygenase (5-LOX) pathway, and does not interfere with the biosynthesis of the specialized pro-resolving mediators as observed with COX inhibitors, providing a new chemotype for effective and safer anti-inflammatory drug development.