Effects of ER-34122, a novel dual 5-lipoxygenase/cyclooxygenase inhibitor, on indices of early articular lesion in MRL/MpJ-lpr/lpr mice

Horizoe, Tatsuo; Nagakura, Naotaka; Chiba, Kenichi; Shirota, Hiroshi; Shinoda, Masanobu; Numata, Hirotoshi; Kobayashi, Seiichi; C, Abe

doi:10.1007/s000110050483

Cited by 19 publications

(13 citation statements)

References 11 publications

(21 reference statements)

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“…in a model of arachidonic acid-induced ear inflammation in mice [36]. ER-34122 also showed antiinflammatory activity in the early stage of spontaneous arthritis using a model of progression of articular lesions in mice [183].…”

Section: Pyrazole Derivativesmentioning

confidence: 96%

New Trends in Dual 5-LOX / COX Inhibition

Leval¹,

Julémont²,

Delarge³

et al. 2002

CMC

109

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Dual inhibitors are drugs able to block both the COX and the 5-LOX metabolic pathways. The interest of developing such compounds is supported by a large number of pharmacological studies. Compared to COX or LOX pathways single inhibitors, dual inhibitors present at least two major advantages. First, dual inhibitors, by acting on the two major arachidonic acid metabolic pathways, possess a wide range of anti-inflammatory activity. Secondly, dual inhibitors appear to be almost exempt from gastric toxicity, which is the most troublesome side effect of COX inhibitors. The mechanism of their gastric-sparing properties is not completely understood, although it has been demonstrated that leukotrienes significantly contribute to the gastric epithelial injury. Finally, both COX and LOX derivatives (prostanoids and leukotrienes, respectively) are involved in other diseases than inflammation such as cancer proliferation where the use of dual inhibitors could be an interesting approach.

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Section: Pyrazole Derivativesmentioning

confidence: 96%

New Trends in Dual 5-LOX / COX Inhibition

Leval¹,

Julémont²,

Delarge³

et al. 2002

CMC

109

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show abstract

“…RWJ-63556, a compound structurally related to the selective COX-2 inhibitor nimesulide, is another potent orally active COX-2/5-LO inhibitor with remarkable antiinflammatory activity in experimental carrageenan-induced inflammation [114]. An interesting activity profile has also been noted for ER-34122 which suppresses progression of PMN infiltration, subsynovial soft tissue edema and multiplication of synovial lining cells in the early stages of arthritis in a mouse model of systemic lupus erythematosus [115,116].…”

Section: Dual Cox-2/5-lo Inhibitorsmentioning

confidence: 97%

New Approaches to the Modulation of the Cyclooxygenase-2 and 5-Lipoxygenase Pathways

González-Périz

Clària

2007

CTMC

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The eicosanoid family comprises a number of biologically active lipid mediators involved in the regulation of inflammation and cancer cell growth. Eicosanoid biosynthesis is usually initiated by the release of arachidonic acid (AA) from membrane phospholipids in response to the interaction of a phospholipase-A(2) (PLA(2)) stimulus with a receptor on the cell membrane. The free released AA is subsequently metabolized by three major enzymatic pathways: the cyclooxygenase (COX), lipoxygenase (LO) and cytochrome P450-dependent pathways. The COX pathway transforms AA into prostaglandins (PGs) and is of particular clinical relevance because it is the main target for non-steroidal anti-inflammatory drugs (NSAIDs). Of interest, COX-2, one of the two COX isoforms, is primarily involved in inflammation and cancer and for this reason selective COX-2 inhibitors have been developed. The efficacy of these compounds is similar to that of traditional NSAIDs but with a lower risk of gastrointestinal toxicity and bleeding. On the other hand, emerging information has recognized the role of other AA metabolites derived from the 5-LO pathway, the leukotrienes (LTs), in mediating and maintaining inflammation. Consequently, drugs able to inhibit 5-LO are now included among the effective pharmacological therapies, especially in asthma and allergic inflammation. Moreover, COX-2 and 5-LO pathways appear to act in parallel in the regulation of cell proliferation and neo-angiogenesis and both COX-2 and 5-LO inhibitors are being investigated as potential anticancer drugs. This review article will update the progress achieved in the knowledge of COX-2 and 5-LO and discuss the emerging approaches for the pharmacological modulation of these pathways.

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“…{[1,5-bis(4-methoxyphenyl)pyrazol-3-yl]dimethoxymethyl}-2-chlorobenzamide) is an orally active dual inhibitor of COX/5-LOX, and in vivo this molecule has shown an enhanced anti-inflammatory effect, when compared with indomethacin, that has been linked to its ability to inhibit the generation of 5-LOX products. ER-34122 suppresses polymorphonuclear neutrophil (PMN) infiltration, subsynovial soft tissue oedema, and multiplication of synovial lining cells in the early stage of arthritis in MRL/1 mice [97]. The maximum plasma concentration of ER-34122 was 0.20 ± 0.10 µM at the dose of 1 mg/kg, which was observed 1 h after oral administration to MRL/mice.…”

Section: S-2474mentioning

confidence: 97%

Dual Acting Anti-Inflammatory Drugs

Leone¹,

Ottani²,

Bertolini

2007

CTMC

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Drugs able to inhibit both cyclooxygenases (COX-1 and COX-2) and 5-lipoxygenase (5-LOX) (dual acting anti-inflammatory drugs) have been designed in order to obtain compounds that retain the activity of classical nonsteroidal anti-inflammatory drugs (NSAIDs) while avoiding their main drawbacks. The classical NSAIDs display their anti-inflammatory action mainly through inhibition of COX and one of their main drawbacks is the curtailed production of gastroprotective prostaglandins (PGs) being associated with the concurrent increased production of the gastro-damaging and bronchoconstrictive leukotrienes (LTs). Leukotrienes and cysteinyl-leukotrienes are moreover pro-inflammatory and increase microvascular permeability. One of the leukotrienes (LTB(4)) is the most potent chemotactic agent and it induces chemotaxis of eosinophils, neutrophils and monocytes in the inflamed tissue, increases superoxide generation and proinflammatory cytokines production. It is further advantageous for a drug to have both COX and 5-LOX inhibiting activities because prostaglandins enhance leukotriene-mediated inflammation. Various structural families of dual inhibitors have been designed and several compounds are currently undergoing clinical development. In the post-COX-2 selective inhibitors era, these dual acting inhibitors may turn out to be promising new drugs to treat inflammatory diseases and possibly other diseases. Indeed, both COX-2 and 5-LOX are also involved in the development and progression of several types of cancer; in these conditions, selective inhibition of COX-2 alone may lead to a shunt of arachidonic acid metabolism towards the leukotriene pathway, and therefore the blockade of both COX-2 and 5-LOX may produce a better anticancer response. In addition, the dual inhibition of both COX and 5-LOX is neuroprotective by suppressing toxic actions of reactive microglia and macrophages, that are increased in aging brain and in age-related degenerative conditions, particularly Alzheimer's and Parkinson's diseases. Finally, the blockade of 5-LOX does not impair the synthesis of lipoxins (LXs), which are mainly produced by further lipoxygenation of 15-HPETE, and which have potent anti-inflammatory properties and can be considered as stop-signal mediators. Leukocyte 15-LOX and platelet 12-LOX by intercellular mechanism via leukocyte/platelet cell-cell interaction convert 15-HPETE into lipoxins.

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Effects of ER-34122, a novel dual 5-lipoxygenase/cyclooxygenase inhibitor, on indices of early articular lesion in MRL/MpJ-lpr/lpr mice

Abstract: These results disclosed that ER-34122, a dual LOX/COX inhibitor, has anti-inflammatory activity in the early stage of the spontaneous arthritis.

Cited by 19 publications

References 11 publications

New Trends in Dual 5-LOX / COX Inhibition

New Trends in Dual 5-LOX / COX Inhibition

New Approaches to the Modulation of the Cyclooxygenase-2 and 5-Lipoxygenase Pathways

Dual Acting Anti-Inflammatory Drugs

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