Substituted phenanthrene imidazoles as potent, selective, and orally active mPGES-1 inhibitors

Côté, Bernard; Boulet, Louise; Brideau, Christine; Claveau, David; Ethier, Diane; Frenette, Richard; Gagnon, Marc; Giroux, André; Guay, Jocelyne; Guiral, Sébastien; Mancini, Joseph A.; Martins, Evelyn; Massé, Frédéric; Méthot, Nathalie; Riendeau, Denis; Rubin, Joel; Xu, Daigen; Yu, Hongping; Ducharme, Yves; Friesen, Richard W.

doi:10.1016/j.bmcl.2007.10.033

Cited by 120 publications

(32 citation statements)

References 17 publications

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“…mPGES-1 represents an attractive target for disease-modifying drug development because its inhibition would specifically diminish PGE 2 production while preserving the production of other PGs. Specific inhibitors of mPGES-1 are actually tested in in vivo studies (67,68). Interestingly, in accord with our results, the use of such inhibitors could improve arthritis treatment by interacting with two major MMPs implicated in cartilage degradation.…”

Section: Figuresupporting

confidence: 80%

Inhibition of Matrix Metalloproteinase-3 and -13 Synthesis Induced by IL-1β in Chondrocytes from Mice Lacking Microsomal Prostaglandin E Synthase-1

Gosset

Pigenet

Salvat

et al. 2010

The Journal of Immunology

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Joint destruction in arthritis is in part due to the induction of matrix metalloproteinase (MMP) expression and their inhibitors, especially MMP-13 and -3, which directly degrade the cartilage matrix. Although IL-1β is considered as the main catabolic factor involved in MMP-13 and -3 expression, the role of PGE2 remains controversial. The goal of this study was to determine the role of PGE2 on MMP synthesis in articular chondrocytes using mice lacking microsomal PGE synthase-1 (mPGES-1), which catalyses the rate-limiting step of PGE2 synthesis. MMP-3 and MMP-13 mRNA and protein expressions were assessed by real-time RT-PCR, immunoblotting, and ELISA in primary cultures of articular chondrocytes from mice with genetic deletion of mPGES-1. IL-1β–induced PGE2 synthesis was dramatically reduced in mPGES-1−/− and mPGES-1+/− compared with mPGES-1+/+ chondrocytes. A total of 10 ng/ml IL-1β increased MMP-3 and MMP-13 mRNA, protein expression, and release in mPGES-1+/+ chondrocytes in a time-dependent manner. IL-1β–induced MMP-3 and MMP-13 mRNA expression, protein expression, and release decreased in mPGES-1−/− and mPGES-1+/− chondrocytes compared with mPGES-1+/+ chondrocytes from 8 up to 24 h. Otherwise, MMP inhibition was partially reversed by addition of 10 ng/ml PGE2 in mPGES-1−/− chondrocytes. Finally, in mPGES-1−/− chondrocytes treated by forskolin, MMP-3 protein expression was significantly decreased compared with wild-type, suggesting that PGE2 regulates MMP-3 expression via a signaling pathway dependent on cAMP. These results demonstrate that PGE2 plays a key role in the induction of MMP-3 and MMP-13 in an inflammatory context. Therefore, mPGES-1 could be considered as a critical target to counteract cartilage degradation in arthritis.

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Section: Figuresupporting

confidence: 80%

Inhibition of Matrix Metalloproteinase-3 and -13 Synthesis Induced by IL-1β in Chondrocytes from Mice Lacking Microsomal Prostaglandin E Synthase-1

Gosset

Pigenet

Salvat

et al. 2010

The Journal of Immunology

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“…First, heparinized blood was preincubated with the thromboxane synthase inhibitor CV4151 (1 M) and the test compounds and stimulated with lipopolysaccharide (10 g/ml) for 5 h, and then formed PGE 2 was separated by RP-HPLC and quantified by ELISA (Koeberle et al, 2009b). In agreement with previous studies, MD52 (which inhibits human mPGES-1 with an IC 50 ϭ 87 nM in cell-free assays) (Côté et al, 2007) maximally suppressed PGE 2 synthesis in whole blood by 48.3 Ϯ 7.7% at high concentrations (2-6 M), whereas celecoxib (20 M) efficiently inhibited PGE 2 formation under these conditions (78.3 Ϯ 8.4%; IC 50 ‫؍‬ 0.87 M) . YS121 concentration-dependently inhibited PGE 2 formation with an IC 50 value of 3 M (Fig.…”

Section: Inhibition Of Mpges-1 By ␣-(N-hexyl)-pirinixic Acid 843supporting

confidence: 54%

“…Pirinixic acid was purchased from Sigma-Aldrich (Deisenhofen, Germany). The mPGES-1 inhibitor MD52 was synthesized according to Côté et al (2007). The compounds were dissolved in DMSO and kept in the dark at Ϫ20°C, and freezing/thawing cycles were kept to a minimum.…”

Section: Methodsmentioning

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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“…We have recently identified a series of selective mPGES-1 inhibitors that are potent and bioavailable (Côté et al, 2007). In the present study, we determined the effects of the lead compound, MF63, on pyresis and inflammatory pain to examine whether selective inhibition of mPGES-1 is sufficient for efficacy.…”

mentioning

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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Substituted phenanthrene imidazoles as potent, selective, and orally active mPGES-1 inhibitors

Cited by 120 publications

References 17 publications

Inhibition of Matrix Metalloproteinase-3 and -13 Synthesis Induced by IL-1β in Chondrocytes from Mice Lacking Microsomal Prostaglandin E Synthase-1

Inhibition of Matrix Metalloproteinase-3 and -13 Synthesis Induced by IL-1β in Chondrocytes from Mice Lacking Microsomal Prostaglandin E Synthase-1

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

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

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Substituted phenanthrene imidazoles as potent, selective, and orally active mPGES-1 inhibitors

Cited by 120 publications

References 17 publications

Inhibition of Matrix Metalloproteinase-3 and -13 Synthesis Induced by IL-1β in Chondrocytes from Mice Lacking Microsomal Prostaglandin E Synthase-1

Inhibition of Matrix Metalloproteinase-3 and -13 Synthesis Induced by IL-1β in Chondrocytes from Mice Lacking Microsomal Prostaglandin E Synthase-1

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

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

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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