Inhibitors of the inducible microsomal prostaglandin E2 synthase (mPGES-1) derived from MK-886

Riendeau, Denis; Aspiotis, Renée; Ethier, Diane; Gareau, Yves; Grimm, Erich L.; Guay, Jocelyne; Guiral, Sébastien; Jûteau, Hélène; Mancini, Joseph A.; Méthot, Nathalie; Rubin, Joel; Friesen, Richard W.

doi:10.1016/j.bmcl.2005.05.027

Cited by 132 publications

(83 citation statements)

References 16 publications

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“…Compound 23 has been reported to have activity inhibiting PGE 2 production in A549 cells with an EC 50 of 490 nM. 17 Therefore, although an upshift in potency might be observed in vivo, this is substantially less than what we observed in the enzyme assay in the presence of octylglucoside. These results may stem from nonspecific binding of inhibitors to the detergent and reduce the ability of the assay to identify mPGES-1 inhibitors.…”

Section: Evaluation Of Reference Inhibitorscontrasting

confidence: 63%

HTRF-Based Assay for Microsomal Prostaglandin E2 Synthase-1 Activity

Goedken¹,

Gagnon²,

Overmeyer³

et al. 2008

SLAS Discovery

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Microsomal prostaglandin E 2 synthase-1 (mPGES-1) catalyzes the formation of prostaglandin E 2 (PGE 2 ) from the endoperoxide prostaglandin H 2 (PGH 2 ). Expression of this enzyme is induced during the inflammatory response, and mouse knockout experiments suggest it may be an attractive target for antiarthritic therapies. Assaying the activity of this enzyme in vitro is challenging because of the unstable nature of the PGH 2 substrate. Here, the authors present an mPGES-1 activity assay suitable for characterization of enzyme preparations and for determining the potency of inhibitor compounds. This plate-based competition assay uses homogenous time-resolved fluorescence to measure PGE 2 produced by the enzyme. The assay is insensitive to DMSO concentration up to 10% and does not require extensive washes after the initial enzyme reaction is concluded, making it a simple and convenient way to assess mPGES-1 inhibition. (Journal of Biomolecular Screening 2008:619-625)

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Section: Evaluation Of Reference Inhibitorscontrasting

confidence: 63%

HTRF-Based Assay for Microsomal Prostaglandin E2 Synthase-1 Activity

Goedken¹,

Gagnon²,

Overmeyer³

et al. 2008

SLAS Discovery

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“…Recombinant microsomal PGES-1 from various species (human, 2 g/ml; rat, 10 g/ml, and guinea pig, 2.5 g/ml) generated in-house was assayed as described previously (Riendeau et al, 2005). Compound or DMSO (final 1%) was added 20 min before the initiation of the reaction with PGH 2 substrate (1 M final concentration) at room temperature.…”

Section: Methodsmentioning

confidence: 99%

MF63 [2-(6-Chloro-1H-phenanthro[9,10-d]imidazol-2-yl)-isophthalonitrile], a Selective Microsomal Prostaglandin E Synthase-1 Inhibitor, Relieves Pyresis and Pain in Preclinical Models of Inflammation

Rowland²,

Clark³

et al. 2008

J Pharmacol Exp Ther

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Microsomal prostaglandin E synthase-1 (mPGES-1) is a terminal prostaglandin E 2 (PGE 2 ) synthase in the cyclooxygenase pathway. Inhibitors of mPGES-1 may block PGE 2 production and relieve inflammatory symptoms. To test the hypothesis, we evaluated the antipyretic and analgesic properties of a novel and selective mPGES-1 inhibitor, MF63 [2-(6-chloro-1H-phenanthro-[9,10-d]imidazol-2-yl)isophthalonitrile], in animal models of inflammation. MF63 potently inhibited the human mPGES-1 enzyme (IC 50 ϭ 1.3 nM), with a high degree (Ͼ1000-fold) of selectivity over other prostanoid synthases. In rodent species, MF63 strongly inhibited guinea pig mPGES-1 (IC 50 ϭ 0.9 nM) but not the mouse or rat enzyme. When tested in the guinea pig and a knock-in (KI) mouse expressing human mPGES-1, the compound selectively suppressed the synthesis of PGE 2 , but not other prostaglandins inhibitable by nonsteroidal anti-inflammatory drugs (NSAIDs), yet retained NSAID-like efficacy at inhibiting lipopolysaccharide-induced pyresis, hyperalgesia, and iodoacetate-induced osteoarthritic pain. In addition, MF63 did not cause NSAID-like gastrointestinal toxic effects, such as mucosal erosions or leakage in the KI mice or nonhuman primates, although it markedly inhibited PGE 2 synthesis in the KI mouse stomach. Our data demonstrate that mPGES-1 inhibition leads to effective relief of both pyresis and inflammatory pain in preclinical models of inflammation and may be a useful approach for treating inflammatory diseases.

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“…For example, biphenyl derivatives of MK-886 are extremely potent in cell-free assays (IC 50 ϭ 3 nM) but lose efficacy in presence of 50% fetal calf serum and fail to suppress PGE 2 formation in human whole blood (Riendeau et al, 2005). In contrast, YS121 suppressed COX-2/mPGES-1-derived PGE 2 formation in human whole blood as well as it did in the cell-free assay.…”

Section: Discussionmentioning

confidence: 99%

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

Koeberle

Rossi²,

Zettl³

et al. 2009

J Pharmacol Exp Ther

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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

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Inhibitors of the inducible microsomal prostaglandin E2 synthase (mPGES-1) derived from MK-886

Cited by 132 publications

References 16 publications

HTRF-Based Assay for Microsomal Prostaglandin E2 Synthase-1 Activity

HTRF-Based Assay for Microsomal Prostaglandin E2 Synthase-1 Activity

MF63 [2-(6-Chloro-1H-phenanthro[9,10-d]imidazol-2-yl)-isophthalonitrile], a Selective Microsomal Prostaglandin E Synthase-1 Inhibitor, Relieves Pyresis and Pain in Preclinical Models of Inflammation

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

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Inhibitors of the inducible microsomal prostaglandin E2 synthase (mPGES-1) derived from MK-886

Cited by 132 publications

References 16 publications

HTRF-Based Assay for Microsomal Prostaglandin E2 Synthase-1 Activity

HTRF-Based Assay for Microsomal Prostaglandin E2 Synthase-1 Activity

MF63 [2-(6-Chloro-1H-phenanthro[9,10-d]imidazol-2-yl)-isophthalonitrile], a Selective Microsomal Prostaglandin E Synthase-1 Inhibitor, Relieves Pyresis and Pain in Preclinical Models of Inflammation

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

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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