Inhibitors of mPGES are considered as

Inhibitors of mPGES-1 are considered as safe alternative to NSAIDs in the treatment of chronic inflammatory diseases that are characterized by excessive PGE2 production (Bahia et al., 2014; Khurana and Jachak, 2016; Koeberle et al., 2016; Korotkova and Jakobsson, 2014; Norberg et al., 2013; Psarra et al., 2017; Samuelsson et al., 2007). They are believed to decrease pro-inflammatory PGE2 biosynthesis with suppressing neither basal levels of PGE2 nor of homeostatic eicosanoids. In contrast, classical NSAIDs (inhibitors of COX-1 and COX-2) and coxibs (selective inhibitors of COX-2) interfere with the formation of a broad spectrum of COX-derived prostanoids. Meanwhile, there is a large body of evidence from pre-clinical studies that substantiates mPGES-1 as favorable target (Koeberle and Werz, 2015; Ozen et al., 2017; Psarra et al., 2017; Samuelsson et al., 2007). Although potentially not free of side-effects, mPGES-1 inhibitors do not cause gastrointestinal complications and they are likely to have a superior renal and cardiovascular safety profile compared to NSAIDs and coxibs. Major challenges in the development of mPGES-1 inhibitors have been i) the poor in vivo efficiency of lipophilic inhibitor N6-Cyclopentyladenosine australia due to high plasma protein binding, ii) disappointing bioavailability and pharmacokinetics, iii) undefined selectivity between PGES isoenzymes, iv) interspecies differences that limit the use of established animal models and v) complex substrate redirections within the bioactive lipid mediator network that require careful risk assessments (Bahia et al., 2014; Koeberle et al., 2016). As far as investigated, high-affinity inhibitors of mPGES-1 all target the active site (Li et al., 2014; Prage et al., 2012; Sjogren et al., 2013). Allosteric inhibitors have not yet been described which might be due to the rigid structure of mPGES-1 which hinders conformational changes (Sjogren et al., 2013). Two selective mPGES-1 inhibitors are meanwhile under clinical investigation. Phase I studies were started for GRC 27864 (with a pyrido[4,3-d]pyrimidin-4(3H)-one scaffold) from Glenmark Pharmaceuticals but results have not yet been reported. Moreover, LY3023703 (structure not disclosed) from Eli Lilly recently completed phase I trials without causing severe adverse effects except for elevated serum aminotransferase levels in one subject (Jin et al., 2016). The clinical candidate efficiently decreased pro-inflammatory PGE2 formation in ex vivo stimulated whole blood but was less efficient in suppressing homeostatic PGE2 biosynthesis (measured as urinary excretion of the main PGE2 metabolite) compared to celecoxib. Most notably, LY3023703 caused a stronger urinary elimination of PGI2 than TxA2, and serum levels of TxB2 (the major metabolite of TxA2 in serum) did not significantly change. This favorable shift in the balance of the two counter-regulators TxA2 and PGI2 supports the hypothesis of mPGES-1 as cardiovascular safe target. In contrast, coxibs block the biosynthesis of COX-2-derived PGI2, which induces vasodilatation and inhibits platelet aggregation, but do not affect the generation of COX-1-derived TxA2 with vasoconstrictory and thrombotic properties (Koeberle and Werz, 2009; Rainsford, 2007). Along these lines, COX-2 inhibitors suppressed PGI2 formation and elevated noradrenaline-induced contractions of human internal mammary arteries in vitro, whereas mPGES-1 inhibitors increased the release of PGI2 from human blood vessels along with reducing vascular contraction (Ozen et al., 2017). Together, current studies further strengthen the hypothesis that the weak but significant increase in cardiovascular incidences by coxibs in clinical studies is related to the PGI2/TxA2 ratio and suggest that mPGES-1 inhibitors might lack these side effects.
Inflammation involves a complex signaling network that offers a broad spectrum of potential targets for therapeutic intervention (Koeberle and Werz, 2014). However, only few key targets, e.g., COX isoenzymes, are located at such central nodes that their selective inhibition is sufficient to relieve or even cure inflammatory diseases. Classical NSAIDs likewise inhibit COX-1 and COX-2 without discriminating between the biosynthesis of different prostanoids (Rainsford, 2007). Among them are lipokines with important physiological functions, e.g., in renal water- and salt balance, gastroprotection, ovum implantation and pregnancy, platelet function and vasoregulation (Funk, 2001; Woodward et al., 2011). Chronic intake of NSAIDs therefore evokes severe side-effects such as gastric ulceration, renal failure and aspirin-triggered asthma (Koeberle and Werz, 2009; Rainsford, 2007). The simplified concept of COX-1-synthesizing physiological levels of prostanoids and COX-2 producing the large amounts of prostanoids at sites of inflammation, led to the development of COX-2-selective coxibs that exhibit potent anti-inflammatory properties and are devoid of gastrointestinal toxicity as the main side-effect of NSAIDs (Grosser et al., 2010; Rainsford, 2007). Meanwhile, it is known that COX-2-derived prostanoids also have important homeostatic functions, among others in protection from tissue damage, (gastric) tissue repair and regeneration (Leone et al., 2007; Ricciotti and FitzGerald, 2011), rendering the long-term treatment with COX-2 inhibitors problematic for patients with colonic damage, pre-existing ulcer or impaired gastrointestinal healing. COX-2 is constitutively expressed in the macula densa of kidneys, mediates the release of renin and regulates renal blood flow, the glomerular filtration rate and vascular homeostasis (Breyer and Harris, 2001; Rios et al., 2012). Moreover, inhibition of COX-2 contributes to the spasmogenic effects of NSAIDs in susceptible asthmatic patients (Sanchez-Borges et al., 2004), slightly increases the blood pressure and enhances the risk for cardiovascular incidences such as myocardial infarction, stroke, congestive heart failure, and sudden cardiac death (Grosser et al., 2010; Patrono, 2016). The latter resulted in the withdrawal of several coxibs, such as rofecoxib (VIOXX®) and valdecoxib (BEXTRA®), in 2004.