Enhanced Efficiency of the Microsomal Prostaglandin E₂ Synthase-1 Inhibitor AGU661 in Human Whole Blood by...

Microsomal prostaglandin E₂ synthase 1 (mPGES-1) is a promising target for treating chronic inflammatory diseases and pain. The novel benzimidazole derivative AGU661 exhibits strong potency as a mPGES-1 inhibitor in a cell-free assay of prostaglandin E₂ (PGE₂) formation with IC₅₀ = 0.22 nM. Comprehensive lipid mediator (LM) metabololipidomics with activated human monocytes and M1- and M2-monocyte-derived macrophages revealed high potency of AGU661 in intact cells with excellent selectivity for suppressing PGE₂ among the broad spectrum of LMs. AGU661 possesses unfavorable physicochemical properties with poor metabolic stability and strong plasma protein binding tendencies, and thus, the compound lost efficiency in complex biological systems like blood. These hurdles could be overcome and the efficiency could be improved by encapsulation of AGU661 into poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles using nanoprecipitation. In comparison to free drug (IC₅₀ > 100 nM), encapsulated AGU661 in PLGA-based solid nanoparticles revealed significantly enhanced potency in human whole blood (IC₅₀ = 1.5 nM). Conclusively, we demonstrate that encapsulation of the mPGES-1 inhibitor AGU661 into polymer-based PLGA nanoparticles represents a suitable approach to improve the anti-inflammatory potential by enhancing its efficiency in complex biological settings like blood.