Targeting Inflammation: Multiple Innovative Ways to Reduce Prostaglandin E ₂

Abstract

The PGE2 pathway is important in inflammation-driven diseases and specific targeting of the inducible mPGES-1 is warranted due to the cardiovascular problems associated with the long-term use of COX-2 inhibitors. This review focuses on patents issued on methods of measuring mPGES-1 activity, on drugs targeting mPGES-1 and on other modulators of free extracellular PGE2 concentration. Perspectives and conclusions regarding the status of these drugs are also presented. Importantly, no selective inhibitors targeting mPGES-1 have been identified and, despite the high number of published patents, none of these drugs have yet made it to clinical trials.

Perspective of microsomal prostaglandin E2 synthase-1 as drug target in inflammation-related disorders

“…Thus, drugs that target mPGES-1 are considered a Page 17 of 59 A c c e p t e d M a n u s c r i p t 17 valuable alternative to NSAIDs/coxibs with improved selectivity and safety profile for treatment of diseases characterized by elevated PGE 2 levels [1,4,59,60]. After the discovery of inducible mPGES-1 in 1999 [30], it became immediately obvious that this PGES might be a favorable drug target and the search for efficient and selective inhibitors began.…”

“…A c c e p t e d M a n u s c r i p t 19 The nature of the reported cell-based assays for evaluation of mPGES-1 inhibitors differs [11,59]. In principle, cell-based assays consist of either primary cells (e.g., peripheral blood mononuclear cells and monocytes), cell lines (e.g.…”

“…Thus, information about plasma protein-binding, cell permeability, intracellular stability and competition with endogenous mPGES-1 regulators are obtained, and the selectivity of the inhibitor can be judged from monitoring the eicosanoid profile. As discussed below, most of the compounds that potently inhibited mPGES-1 in the cell-free assay failed in cell-based test systems (in particular in whole blood) because of lack of activity seemingly due to unspecific (plasma)protein binding [11,59].…”

“…pharmacophore modelling and virtual screening) enabled the discovery of different chemical classes of mPGES-1 inhibitors, which is not subject of this commentary. exogenously added as substrate [11,59]. Principle of the test system is the direct conversion of PGH 2 to PGE 2 catalyzed by mPGES-1, where PGE 2 (native or radiolabeled) is monitored by RP-HPLC (with UV or radiometric detection) [30,61], ELISA, or by photometric measurement of NADH produced by 15-hydroxy-PG dehydrogenase during reduction of PGE 2 [62].…”

Fructus sophorae attenuates secretion of proinflammatory mediators and cytokines through the modulation of NF-κB and MAPK signaling pathways in LPS-stimulated RAW 264.7 macrophages

“…The presence of NO and PGE 2 is widely used as indicators of microphage activation among many inflammatory mediators (Joubert and Malan 2011;Norberg et al 2013). iNOS and COX-2 were expressed in activated macrophages, mediating the synthesis of NO and PGE 2 released into the culture medium.…”