Microsomal Prostaglandin E2 Synthase-1 (mPGES-1): A Novel Anti-Inflammatory Therapeutic Target

Richard W. Friesen*† and Joseph A. Mancini‡

The use of NSAIDsa (nonselective inhibitors of cyclooxygenase (COX-1 and COX-2) and coxibs (selective inhibitors of COX-2) is a mainstay of anti-inflammatory and analgesic therapy. Since coxibs and NSAIDs intervene in the prostaglandin (PG) pathway at the level of PGH2 synthesis, the question that arises is whether similar or greater, anti-inflammatory and analgesic efficacy might be obtained by selective inhibition of one of the downstream PG synthesizing enzymes (Figure 1). Present thinking is that COX-2 derived PGE2, acting on one or more of its cellular receptors EP1 through EP4, is the major mediator of inflammatory pain.1 However, the suggestion that PGI2 is also a significant contributor in the inflammatory process is supported by preclinical studies using PGI2 receptor (IP) deficient mice and selective IP antagonists.2, 3 The availability of a pharmacologically active molecule capable of selective inhibition of PGE2 synthesis may provide the answer to the question of whether this therapeutic approach would exhibit anti-inflammatory and analgesic efficacy equal to that of selective COX-2 inhibitors or NSAIDs. a. Abbreviations: AA, arachidonic acid; CAIA, collagen antibody induced arthritis; CHO, Chinese hamster ovary; CIA, collagen induced arthritis; COX, cyclooxygenase; coxib, selective inhibitor of COX-2; CSF, cerebrospinal fluid; EIA, enzyme immunoassay; FBS, fetal bovine serum; FLAP, 5-lipoxygenase activating protein; GSH, glutathione; HTS, high throughput screen; IL, interleukin; IP, prostacyclin receptor; JAK, Janus kinase; KI, knock-in; KO, knockout; LDLR, low density lipoprotein receptor; LPS, lipopolysaccharide; LT, leukotriene; MAPEG, membrane associated proteins involved in eicosanoid and glutathione metabolism; mGST, microsomal glutathione transferase; NSAID, nonsteroidal anti-inflammatory drug; PG, prostaglandin; PGES, prostaglandin E2 synthase; PPAR, peroxisome proliferator-activated receptor; QSAR, quantitative structure-activity relationship; TX, thromboxane; WT, wild type.

COX-1 and COX-2 are the enzymes that catalyze the formation of the unstable cyclic peroxide PGH2 by the bis-oxygenation of arachidonic acid. PGE2 is synthesized from PGH2 by the PGE2 synthase enzymes. The first PGE2 synthase was identified in 1999 and termed microsomal PGE synthase-1 (mPGES-1).4 Two other PGE2 synthases have been cloned: cytosolic PGES (cPGES) and membrane PGES-2 (mPGES-2).5, 6 Both cPGES and mPGES-2 are constitutively expressed enzymes with cPGES coupling through COX-1 and with mPGES-2 coupling through both COX-1 and COX-2.6, 7 The mPGES-1 enzyme, which is inducible by various inflammatory stimuli, is primarily coupled to COX-2.8 Initial studies from several reports of mPGES-1 null mice define a significant role for this enzyme in mediating pain, inflammation, fever, arthritis, atherosclerosis, stroke, and cancer. A number of excellent reviews have summarized the biology and pharmacology of mPGES-1 and provide a firm rationale for targeting this enzyme in drug development.9, 10 Therefore, the following sections will only briefly outline the rationale behind the advocacy of this particular enzyme as the key player in these therapeutic areas, and the focus of this review will be on summarizing the progress to date in the development of selective mPGES-1 inhibitors and their efficacy in preclinical animal models of inflammation.