(Methoxyalkyl)thiazoles: a new series of potent, selective, and orally active 5-lipoxygenase inhibitors displaying high enantioselectivity

Bird, T. G. C.; Bruneau, Pierre; Crawley, G. C.; Edwards, Martin P.; Foster, Stephen J.; Girodeau, J.-M.; Kingston, John F.; McMillan, R. M.

doi:10.1021/jm00111a038

Cited by 56 publications

(21 citation statements)

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“…Inhibition of the enzyme activity can take effect by competitive binding to the active site or by binding to an allosteric binding site that regulates the activity of the enzyme. The (methoxyalkyl)thiazole (ICI211965) ( Figure 2 ) selectively inhibits 5-LOX activity, which reduces LTC4 and LTB4 synthesis in animal and human blood samples [ 99 ]. Unfortunately, steady-state kinetic analyses of this compound for 5-LOX have not been successfully performed and therefore it has not been possible to determine whether the inhibition is competitive with the substrate arachidonic acid or not [ 100 ].…”

Section: Lipoxygenase Inhibitorsmentioning

confidence: 99%

Inflammation, Cancer and Oxidative Lipoxygenase Activity are Intimately Linked

Wisastra

Dekker

2014

Cancers

148

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Cancer and inflammation are intimately linked due to specific oxidative processes in the tumor microenvironment. Lipoxygenases are a versatile class of oxidative enzymes involved in arachidonic acid metabolism. An increasing number of arachidonic acid metabolites is being discovered and apart from their classically recognized pro-inflammatory effects, anti-inflammatory effects are also being described in recent years. Interestingly, these lipid mediators are involved in activation of pro-inflammatory signal transduction pathways such as the nuclear factor κB (NF-κB) pathway, which illustrates the intimate link between lipid signaling and transcription factor activation. The identification of the role of arachidonic acid metabolites in several inflammatory diseases led to a significant drug discovery effort around arachidonic acid metabolizing enzymes. However, to date success in this area has been limited. This might be attributed to the lack of selectivity of the developed inhibitors and to a lack of detailed understanding of the functional roles of arachidonic acid metabolites in inflammatory responses and cancer. This calls for a more detailed investigation of the activity of arachidonic acid metabolizing enzymes and development of more selective inhibitors.

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Section: Lipoxygenase Inhibitorsmentioning

confidence: 99%

Inflammation, Cancer and Oxidative Lipoxygenase Activity are Intimately Linked

Wisastra

Dekker

2014

Cancers

148

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“…The methoxyalkylthiazole ICI 211965 is a potent inhibitor of 5-lipoxygenase and does not inhibit cyclooxygenases [55,56]. The derivative ICID 2138 is at least 10 times more potent (ex vivo ED 50 for 5-lipoxygenase inhibition = 1 mg/kg after oral dosing), and no inhibition of cyclooxygenases has been observed even at concentrations up to 20,000 fold higher than those that inhibit 5-lipoxygenase [47].…”

Section: A Reappraisal Of the Role Of Lipoxy-genasesmentioning

confidence: 99%

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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“…The methoxyalkylthiazole ICI 211965 is a potent inhibitor of 5-lipoxygenase and does not inhibit cyclooxygenases [100,101]. The methoxyalkylthiazole ICI 211965 is a potent inhibitor of 5-lipoxygenase and does not inhibit cyclooxygenases [100,101].…”

Section: Role Of Lipoxygenasesmentioning

confidence: 99%

Selective COX-2 Inhibitors and Dual Acting Anti-inflammatory Drugs: Critical Remarks

Bertolini¹

2002

cmc

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Non steroidal anti-inflammatory drugs (NSAIDs) are still the most commonly used remedies for rheumatic diseases. But NSAIDs produce serious adverse effects, the most important being gastric injury up to gastric ulceration and renal damage.Several strategies have been adopted in order to avoid these shortcomings, expecially gastrointestinal toxicity. So, non steroidal anti-inflammatory drugs have been associated with gastroprotective agents that counteract the damaging effects of prostaglandin synthesis suppression: however, a combination therapy introduces problems of pharmacokinetics, toxicity, and patient's compliance. Also incorporation of a nitric oxide (NO)generating moiety into the molecule of several NSAIDs was shown to greatly attenuate their ulcerogenic activity: however, several findings suggest a possible involvement of NO in the pathogenesis of arthritis and subsequent tissue destruction.A most promising approach seemed to be the preparation of novel NSAIDs, specific for the inducible isoform of cyclooxygenase (COX-2): they appear to be devoid of gastrointestinal toxicity, in that they spare mucosal prostaglandin synthesis.However, a number of recent studies raised serious questions about the two central tenets that support this approach, namely that the prostaglandins that mediate inflammation and pain are produced solely via COX-2 and that the prostaglandins that are important in gastrointestinal and renal function are produced solely via COX-1. So, increasing evidence shows that COX-2 (not only COX-1) also plays a physiological role in several body functions and that, conversely, COX-1 (not only COX-2) may also be induced at sites of inflammation.Moreover, COX-2 selective NSAIDs have lost the cardiovascular protective effects of non-selective NSAIDs, effects which are mediated through COX-1 inhibition (in addition, COX-2 has a role in sustaining vascular prostacyclin production).The products generated by the 5-lipoxygenase pathway (leukotrienes) are particularly important in inflammation: indeed, leukotrienes increase microvascular permeability and are potent chemotactic agents; moreover, inhibition of 5-lipoxygenase indirectly reduces the expression of TNF-α (a cytokine that plays a key role in inflammation). This explains the efforts to obtain drugs able to inhibit both 5-lipoxygenase and cyclooxygenases: the so-called dual acting anti-inflammatory drugs. Such compounds retain the activity of classical NSAIDs, while avoiding their main drawbacks, in that curtailed production of gastroprotective prostaglandins is associated with a concurrent curtailed production of the gastro-damaging and bronchoconstrictive leukotrienes.Moreover, thanks to their mechanism of action, dual acting anti-inflammatory drugs could not merely alleviate symptoms of rheumatic diseases, but might also satisfy, at least in part, the criteria of curative drugs. Indeed, leukotrienes are pro-inflammatory, increase microvascular permeability, are potent chemotactic agents and attract eosinophils, neutrophils and monocytes into t...

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(Methoxyalkyl)thiazoles: a new series of potent, selective, and orally active 5-lipoxygenase inhibitors displaying high enantioselectivity

Cited by 56 publications

References 1 publication

Inflammation, Cancer and Oxidative Lipoxygenase Activity are Intimately Linked

Inflammation, Cancer and Oxidative Lipoxygenase Activity are Intimately Linked

Dual Acting Anti-Inflammatory Drugs

Selective COX-2 Inhibitors and Dual Acting Anti-inflammatory Drugs: Critical Remarks

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