ML 3000 reduces gastric prostaglandin synthesis without causing mucosal injury

Wallace, John L.; Carter, L.; McKnight, Webb; Tries, S.; Laufer, Stefan

doi:10.1016/0014-2999(94)90814-1

Cited by 53 publications

(40 citation statements)

References 18 publications

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“…1), and may be involved in the gastrointestinal toxicity of traditional NSAIDs. In agreement with this hypothesis, compounds capable of inhibiting both 5-lipoxygenase and cyclooxygenase [25] have shown to be potent antiinflammatory agents [26] with improved gastric tolerability when compared to non-selective inhibitors of cyclooxygenases [27,28]. Furthermore ML3000, a dual 5-LOX/COX inhibitor currently in phase III clinical trials for the treatment of osteoarthritis and rheumatoid arthritis, was recently shown to effectively inhibit cellular adhesion and transcellular synthesis of cys-LT in neutrophil/platelet coincubations [29].…”

Section: A Rationale For the Use Of 5-lox/cox Dual Inhibitors In Inflmentioning

confidence: 81%

Neutrophils, Endothelial Cells, and Cysteinyl Leukotrienes: A New Approach to Neutrophil-Dependent Inflammation?

Sala

Folco

2001

Biochemical and Biophysical Research Communications

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Section: A Rationale For the Use Of 5-lox/cox Dual Inhibitors In Inflmentioning

confidence: 81%

Neutrophils, Endothelial Cells, and Cysteinyl Leukotrienes: A New Approach to Neutrophil-Dependent Inflammation?

Sala

Folco

2001

Biochemical and Biophysical Research Communications

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“…In fact, licofelone markedly improved gastrointestinal tolerability in animal models and offered gastroprotection against NSAIDs-induced gastropathy (Wallace et al, 1994;Kulkarni and Singh, 2007). In healthy volunteers, licofelone showed significantly superior gastric tolerability and a lower incidence of ulcers compared with naproxen (Bias et al, 2004).…”

Section: Licofelone Inhibits Mpges-1 Discussionmentioning

confidence: 99%

Licofelone Suppresses Prostaglandin E₂ Formation by Interference with the Inducible Microsomal Prostaglandin E₂ Synthase-1

Koeberle

Siemoneit²,

Bühring³

et al. 2008

J Pharmacol Exp Ther

153

237

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The anti-inflammatory drug licofelone [ϭML3000; 2-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl] acetic acid], currently undergoing phase III trials for osteoarthritis, inhibits the prostaglandin (PG) and leukotriene biosynthetic pathway. Licofelone was reported to suppress the formation of PGE 2 in various cell-based test systems, but the underlying molecular mechanisms are not entirely clear. Here, we examined the direct interference of licofelone with enzymes participating in PGE 2 biosynthesis, that is, cyclooxygenase (COX)-1 and COX-2 as well as microsomal PGE 2 synthase (mPGES)-1. Licofelone concentration-dependently inhibited isolated COX-1 (IC 50 ϭ 0.8 M), whereas isolated COX-2 was less affected (IC 50 Ͼ 30 M). However, licofelone efficiently blocked the conversion of PGH 2 to PGE 2 mediated by mPGES-1 (IC 50 ϭ 6 M) derived from microsomes of interleukin-1␤-treated A549 cells, being about equipotent to 3-[1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl]-2,2-dimethylpropanoic acid (MK-886), a well recognized mPGES-1 inhibitor. In intact interleukin-1␤-treated A549 cells, licofelone potently (IC 50 Ͻ 1 M) blocked formation of PGE 2 in response to calcimycin (A23187) plus exogenous arachidonic acid, but the concomitant generation of 6-keto PGF 1␣ , used as a biomarker for COX-2 activity, was not inhibited. We conclude that licofelone suppresses inflammatory PGE 2 formation preferentially by inhibiting mPGES-1 at concentrations that do not affect COX-2, implying an attractive and thus far unique molecular pharmacological dynamics as inhibitor of COX-1, the 5-lipoxygenase pathway, and of mPGES-1.Prostaglandins (PGs) and leukotrienes are powerful bioactive lipid mediators that are involved not only in numerous homeostatic biological functions but also in inflammation (Funk, 2001). The biosynthesis of PGs is initialized by COX isoenzymes, namely, COX-1, a constitutively expressed enzyme in numerous cell types thought to provide PGs mainly for physiological functions; and COX-2, an inducible isoform in inflammatory cells, primarily producing PGs relevant for inflammation, fever, and pain (Hawkey, 1999). After conversion of arachidonic acid to PGH 2 by COX enzymes, PGH 2 is subsequently isomerized by three different PGE 2 synthases to PGE 2 . Whereas the cytosolic PGE 2 synthase (cPGES) and the membrane-bound PGE 2 synthase (mPGES)-2 are constitutive enzymes, the mPGES-1 is an inducible isoform (Samuelsson et al., 2007). Cotransfection experiments of COX-1/2 with PGES isoenzymes imply that select molecular interactions between COX and PGES isoenzymes cause preferential functional coupling (Murakami et al., 2000;Samuelsson et al., 2007). Thus, cPGES uses PGH 2 produced by COX-1, whereas mPGES-1 receives PGH 2 from COX-2. PGE 2 plays a major role in the pathophysiology of inflammation, pain, and pyresis, but it also regulates physiological functions in the gastrointestinal tract, the kidney, and in the immune and nervous system (Smith, 1989). The nonsteroidal anti-inflamm...

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“…In addition, dual inhibitors appear to exert some diseasemodifying activity and, for example, they may stop disease progression by reducing the expression of matrix metalloproteinase-13 and IL-1␤ (Celotti and Durand, 2003). Moreover, dual inhibitors have an excellent gastrointestinal profile, much better than that for conventional nonsteroidal antiinflammatory drugs and equivalent to that of selective COX-2 inhibitors Wallace et al, 1994). Another interesting finding of our study was that pharmacological COX-2 inhibition in 5-LO-deficient mice resulted in a reduction of hepatic MCP-1 expression.…”

mentioning

confidence: 99%

Comparative Protection against Liver Inflammation and Fibrosis by a Selective Cyclooxygenase-2 Inhibitor and a Nonredox-Type 5-Lipoxygenase Inhibitor

Horrillo

Planagumà²,

González-Périz³

et al. 2007

J Pharmacol Exp Ther

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In this study, we examined the relative contribution of cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LO), two major proinflammatory pathways up-regulated in liver disease, to the progression of hepatic inflammation and fibrosis. Separate administration of 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (SC-236), a selective COX-2 inhibitor, and CJ-13,610, a 5-LO inhibitor, to carbon tetrachloride-treated mice significantly reduced fibrosis as revealed by the analysis of Sirius Red-stained liver sections without affecting necroinflammation. Conversely, combined administration of SC-236 and 4-[3-[4-(2-methylimidazol-1-yl)-phenylthio]]phenyl-3,4,5,6-tetrahydro-2H-pyran-4-carboxamide (CJ-13,610) reduced both necroinflammation and fibrosis. These findings were confirmed in5-LO-deficient mice receiving SC-236, which also showed reduced hepatic monocyte chemoattractant protein 1 expression. Interestingly, SC-236 and CJ-13,610 significantly increased the number of nonparenchymal liver cells with apoptotic nuclei (terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive). Additional pharmacological profiling of SC-236 and CJ-13,610 was performed in macrophages, the primary hepatic inflammatory cell type. In these cells, SC-236 inhibited prostaglandin (PG) E 2 formation in a concentration-dependent manner, whereas CJ-13,610 blocked leukotriene B 4 biosynthesis. Of note, the simultaneous addition of SC-236 and CJ-13,610 resulted in a higher inhibitory profile on PGE 2 biosynthesis than the dual COX/5-LO inhibitor licofelone. These drugs differentially regulated interleukin-6 mRNA expression in macrophages. Taken together, these findings indicate that both COX-2 and 5-LO pathways are contributing factors to hepatic inflammation and fibrosis and that these two pathways of the arachidonic acid cascade represent potential targets for therapy.

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ML 3000 reduces gastric prostaglandin synthesis without causing mucosal injury

Cited by 53 publications

References 18 publications

Neutrophils, Endothelial Cells, and Cysteinyl Leukotrienes: A New Approach to Neutrophil-Dependent Inflammation?

Neutrophils, Endothelial Cells, and Cysteinyl Leukotrienes: A New Approach to Neutrophil-Dependent Inflammation?

Licofelone Suppresses Prostaglandin E₂ Formation by Interference with the Inducible Microsomal Prostaglandin E₂ Synthase-1

Comparative Protection against Liver Inflammation and Fibrosis by a Selective Cyclooxygenase-2 Inhibitor and a Nonredox-Type 5-Lipoxygenase Inhibitor

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ML 3000 reduces gastric prostaglandin synthesis without causing mucosal injury

Cited by 53 publications

References 18 publications

Neutrophils, Endothelial Cells, and Cysteinyl Leukotrienes: A New Approach to Neutrophil-Dependent Inflammation?

Neutrophils, Endothelial Cells, and Cysteinyl Leukotrienes: A New Approach to Neutrophil-Dependent Inflammation?

Licofelone Suppresses Prostaglandin E2 Formation by Interference with the Inducible Microsomal Prostaglandin E2 Synthase-1

Comparative Protection against Liver Inflammation and Fibrosis by a Selective Cyclooxygenase-2 Inhibitor and a Nonredox-Type 5-Lipoxygenase Inhibitor

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Licofelone Suppresses Prostaglandin E₂ Formation by Interference with the Inducible Microsomal Prostaglandin E₂ Synthase-1