Novel potent benzimidazole-based microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitors derived from BRP-201 that also inhibit leukotriene C4 synthase

Microsomal prostaglandin E2 synthase-1 (mPGES-1) is recognized as a promising therapeutic target for next-generation anti-inflammatory drugs to treat inflammatory diseases. In this study, we report the identification of new, potent and selective inhibitors of human mPGES-1 such as compounds 10, 31 and 49 with IC50 of 0.03–0.09 μM in a cell-free assay of PGE2 production. Compound 10 and 49 also inhibited leukotriene C4 synthase (LTC4S) at sub-μM concentrations (IC50 = 0.7 and 0.4 μM, respectively), affording compounds dually targeting inflammatory PGE2 and cysteinyl leukotriene (cys-LT) biosynthesis. However, compound 31 showed substantial selectivity towards mPGES-1 (IC50 = 0.03 μM) with a decreased inhibitory activity on LTC4S (IC50 = 2.8 μM), and also on other related targets such as FLAP and 5-LO. These oxadiazole thione-benzimidazole derivatives warrant further exploration of new and alternative analogs that may lead to the identification of novel derivatives with potent anti-inflammatory properties. [Display omitted] •New oxadiazole thione-benzimidazole derivatives as mPGES-1 and LTC4S inhibitors are reported.•Compounds 10, 31 and 49 showed potent mPGES-1 inhibitory activity with IC50 of 0.03–0.09 μM.•Compounds 10 and 49 also inhibited LTC4S activity with IC50 of 0.7 and 0.4 μM.