The Molecular Pharmacology and In Vivo Activity of 2-(4-Chloro-6-(2,3-dimethylphenylamino)pyrimidin-2-ylthio)octanoic acid (YS121), a Dual Inhibitor of Microsomal Prostaglandin E₂ Synthase-1 and 5-Lipoxygenase

Abstract

The microsomal prostaglandin E 2 synthase (mPGES)-1 is one of the terminal isoenzymes of prostaglandin (PG) E 2 biosynthesis. Pharmacological inhibitors of mPGES-1 are proposed as an alternative to nonsteroidal anti-inflammatory drugs. We recently presented the design and synthesis of a series of pirinixic acid derivatives that dually inhibit mPGES-1 and 5-lipoxygenase. Here, we investigated the mechanism of mPGES-1 inhibition, the selectivity profile, and the in vivo activity of ␣-(n-hexyl)-substituted pirinixic acid [YS121; 2-(4-chloro-6-(2,3-dimethylphenylamino)pyrimidin-2-ylthio)octanoic acid)] as a lead compound. In cell-free assays, YS121 inhibited human mPGES-1 in a reversible and noncompetitive manner (IC 50 ϭ 3.4 M), and surface plasmon resonance spectroscopy studies using purified in vitro-translated human mPGES-1 indicate direct, reversible, and specific binding to mPGES-1 (K D ϭ 10 -14 M). In lipopolysaccharide-stimulated human whole blood, PGE 2 formation was concentration dependently inhibited (IC 50 ϭ 2 M), whereas concomitant generation of the cyclooxygenase (COX)-2-derived thromboxane B 2 and 6-keto PGF 1␣ and the COX-1-derived 12(S)-hydroxy-5-cis-8,10-transheptadecatrienoic acid was not significantly reduced. In carrageenan-induced rat pleurisy, YS121 (1.5 mg/kg i.p.) blocked exudate formation and leukocyte infiltration accompanied by reduced pleural levels of PGE 2 and leukotriene B 4 but also of 6-keto PGF 1␣ . Taken together, these results indicate that YS121 is a promising inhibitor of mPGES-1 with anti-inflammatory efficiency in human whole blood as well as in vivo.Prostaglandins (PGs) are potent lipid mediators that promote inflammatory reactions but also possess homeostatic functions (Funk, 2001). Their biosynthesis involves oxygenation of arachidonic acid by cyclooxygenase (COX)-1 or -2 to PGH 2 and further conversion by PG synthases to the respective PGs (Funk, 2001). Inhibition of COX-1 and -2 by nonsteroidal anti-inflammatory drugs and selective suppression of COX-2 by coxibs are common and effective strategies for the therapy of inflammatory disorders, fever, and pain, but their long-term use is associated with severe side effects (Rainsford, 2007). Unselective COX-1/2 inhibitors may cause gastric toxicity, whereas an increased cardiovascular risk in This work was supported in part by Carl Zeiss GmbH (to C.P.). Article, publication date, and citation information can be found at

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

“…Comprehensive SAR studies and target-oriented design led to promising leads such as YS121 [101], compound 29 [102] and compound 16 [103] (Table 2) with potent anti-inflammatory efficacy and repression of LT and PGE 2 levels in vivo in relevant animal models (e.g., carrageenan-induce pleurisy in rats, zymosan-induced peritonitis in mice) without marked repression of COX products such as 6-keto PGF 1α . Note that these compounds also repressed anti-inflammatory properties and significantly reduced LTB 4 and PGE 2 levels (but not 6-keto PGF 1α ) in vivo (mouse paw edema and rat pleurisy) [104,105] (Table 2).…”

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“…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).…”

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“…In addition, pirinixic acid 7 [190] and 2-mercaptohexanoic acid 8 [191] derivatives have been reported as 5-LOX/mPGES-1 dual inhibitors. In comparison with indomethacin (5 mg/kg), YS121 (1.5 mg/kg) was as efficient in reducing exudates formation and leukocyte infiltration with reduced pleural levels of PGE 2 and LTB 4 in the carrageenan-induced rat pleurisy model [192]. Recently virtual screening using a comparative model of the human 5-LOX led to the discovery of new 5-LOX/mPGES-1 dual inhibitors 9 and 10 possessing novel scaffolds [193].…”