Identification and Characterization of Novel Microsomal Prostaglandin E Synthase-1 Inhibitors for Analgesia

Abstract

Prostaglandin (PG) E 2 plays a critical role in eliciting inflammation. Nonsteroidal anti-inflammatory drugs and selective inhibitors of cyclooxygenase, which block PGE 2 production, have been used as key agents in treating inflammation and pain associated with arthritis and other conditions. However, these agents have significant side effects such as gastrointestinal bleeding and myocardial infarction, since they also block the production of prostanoids that are critical for other normal physiologic functions. Microsomal prostaglandin E 2 synthase-1 is a membrane-bound terminal enzyme in the prostanoid pathway, which acts downstream of cyclooxygenase 2 and is responsible for PGE 2 production during inflammation. Thus, inhibition of this enzyme would be expected to block PGE 2 production without inhibiting other prostanoids and would provide analgesic efficacy without the side effects. In this report, we describe novel microsomal prostaglandin E 2 synthase-1 inhibitors that are potent in blocking PGE 2 production and are efficacious in a guinea pig monoiodoacetate model of arthralgia. These molecules may be useful in treating the signs and symptoms associated with arthritis.

Breaking barriers to novel analgesic drug development

“…Microsomal prostaglandin E2 synthase-1 is responsible for PGE2 production during inflammation as the terminal enzyme in the prostanoid pathway, acting downstream of cyclooxygenase 2 238 . PGE2 is a major inflammatory sensitizer of nociceptors, and mPGES1 inhibition using MF-63 [2-(6-chloro-1H-phenanthro-[9,10-d]imidazol-2-yl)isophthalonitrile] and two novel 2-Acylaminoimidazole inhibitors has been shown to reduce inducible PGE synthesis without suppressing prostacyclin generation.…”

Potential Antifungal Targets against a Candida Biofilm Based on an Enzyme in the Arachidonic Acid Cascade—A Review

“…Current evidence suggests that cytosolic PGES (cPGES) and microsomal prostaglandin E synthase-2 (mPGES-2) are constitutively expressed in cells and are coupled with COX-1 and COX-1/-2, respectively (Murakami et al, 2003). Microsomal PGES-1 (MPGES-1) is stimulus inducible and specifically couples with COX-2; it is the terminal enzyme in the biosynthesis of PGE 2 and, ideally, does not affect the formation of other housekeeping PGs (Koeberle et al, 2010; Chandrasekhar et al, 2016). In Chandrasekhar's research, mPGES-1 exhibits selective inhibition of PGE 2 in human epithelial cells, carcinoma cells (A549) and human whole blood treated with lip polysaccharides (LPS; Chandrasekhar et al, 2016).…”

“…Microsomal PGES-1 (MPGES-1) is stimulus inducible and specifically couples with COX-2; it is the terminal enzyme in the biosynthesis of PGE 2 and, ideally, does not affect the formation of other housekeeping PGs (Koeberle et al, 2010; Chandrasekhar et al, 2016). In Chandrasekhar's research, mPGES-1 exhibits selective inhibition of PGE 2 in human epithelial cells, carcinoma cells (A549) and human whole blood treated with lip polysaccharides (LPS; Chandrasekhar et al, 2016). An mPGES-1 knock-out experiment shows that mPGES-1 deficient mice cannot induce the expression of mPGES-1 in response to LPS (Uematsu et al, 2002; Trebino et al, 2003).…”

“…In various mice and rat inflammation models, mPGES-1 plays a pathogenic role in tumorigenesis (Fahmi, 2004), inflammation (Trebino et al, 2003; Iyer et al, 2009), and bone metabolism (Saha et al, 2005). An mPGES-1 inhibitor was found to be efficacious for arthralgia (Chandrasekhar et al, 2016) and is regarded as a promising influenza therapeutic target because of its ability to suppress the induction of pro-inflammatory genes (Park et al, 2016). In addition, mPGES-1 participated in various pathophysiological states in which both COX-1 and COX-2 are involved, implying that the role of the mPGES-1 enzyme is partially similar to that of COX (Murakami et al, 2002, 2003; Tanioka et al, 2003).…”

Analgesic and anti‐inflammatory properties of novel, selective, and potent EP4 receptor antagonists

“…; Chandrasekhar et al. ). NSAIDs and selective cyclooxygenase inhibitors (coxibs) provide symptomatic relief in human arthritis by blocking the production of PGE 2 through the inhibition of cyclooxygenase‐1and/or cyclooxygenase‐2 (FitzGerald ; Rainsford ).…”