Acetohydroxamic acids as potent, selective, orally active 5-lipoxygenase inhibitors

Jackson, W. P. U.; Islip, P. J.; Kneen, G.; Pugh, Ashley W.; Wates, Peter J.

doi:10.1021/jm00398a001

Cited by 58 publications

(19 citation statements)

References 3 publications

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“…One of the most powerful metal ligand groups is the hydroxamic acid moiety: hydroxamic acids and their close derivatives N-hydroxyureas (zileuton; ABT-761) show modest (10-40-fold) selectivity for inhibition of 5-lipoxygenase [53,54].…”

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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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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“…A decrease in reaction time indicated an increase in hyperalgesia. (N-[3{5,6,7,8-tetrahydro-2-naphthyl) prop-2-enyl]-acetohydroxamic acid) were synthesized as described by Jackson et al (1988). Indomethacin was obtained from Merck Sharpe and Dohme.…”

Section: Carrageenin-induced Hyperalgesiamentioning

confidence: 99%

Selective inhibition of arachidonate 5‐lipoxygenase by novel acetohydroxamic acids: effects on acute inflammatory responses

Higgs

Follenfant

Garland

1988

British J Pharmacology

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1 Two selective inhibitors of arachidonate 5-lipoxygenase, BW A4C and BW A797C, have been studied for their effects on acute inflammatory responses following oral administration to rats and mice. 2 The concentrations of the lipoxygenase product leukotriene B4 (LTB4) in 6 h inflammatory exudates, induced in rats by the subcutaneous implantation of carrageenin-soaked polyester sponges, were reduced dose-dependently by BW A4C (ED5o = 2.6 mgkg-') or BW A797C (ED50= 14.3 mg kg 1). 3 BW A4C and BW A797C had little or no effect on prostaglandin E2 (PGE2) concentrations in inflammatory exudates (ED50s > 100 mg kg-1). 4 Doses of up to 200mgkg-1 of either BW A4C or BW A797C had no effect on carrageenin-induced oedema in rat paws. 5 BW A4C and BW A797C had little or no effect on carrageenin-induced hyperalgesia in rats or phenyl-benzoquinone-induced writhing in mice.6 Yeast-induced pyrexia in rats was reduced by both BW A4C (ED50 = 32mgkg-1) and BW A797C (ED5o = 23 mg kg-1).7 The accumulation of leucocytes in sponge exudates was reduced dose-dependently by BW A4C (ED5o = 54mgkg-1) and BW A797C (ED50 = 16.7mgkg-1).8 The selective lipoxygenase inhibitors BW A4C and BW A797C do not suppress inflammatory oedema or pain although they are anti-pyretic and they do inhibit leucocyte migration. There is not, however, a close agreement between these in vivo activities and their potencies as lipoxygenase inhibitors.

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“…The acetohydroxamic acids, BW A4C and BW A137C (N-(3-phenoxycinnamyl) and N-(4-benzyloxybenzyl)-acetohydroxamic acid) were synthesized as described by Jackson et al (1988) …”

Section: Drugs and Materialsmentioning

confidence: 99%

Failure of the inhibition of rat gastric mucosal 5‐lipoxygenase by novel acetohydroxamic acids to prevent ethanol‐induced damage

Boughton‐Smith

Whittle

1988

British J Pharmacology

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The role of leukotriene B4 (LTB4) and LTC4 as mediators of gastric mucosal damage following ethanol challenge in vivo has been investigated using two selective 5‐lipoxygenase inhibitors, BW A4C and BW A137C. Oral administration of ethanol to rats in vivo, induced macroscopic damage to the gastric mucosa and markedly increased the formation of the 5‐lipoxygenase products, LTB4 and LTC4, from the mucosa ex vivo. Pretreatment with the acetohydroxamic acids BW A4C and BW A137C (5–50 mg kg−1 p.o.) dose‐dependently reduced ethanol‐stimulated LTB4 and LTC4 formation by the gastric mucosa, with an ID50 of approximately 5 mg kg−1 p.o. A single oral dose of BW A4C (20 mg kg−1) induced near‐maximal inhibition of mucosal LTB4 formation within 30 min, which was well maintained for 5h, whereas BW A137C (20 mg kg−1 p.o.) induced maximal inhibition between 30 and 60 min after administration, which then diminished over the subsequent 5 h. The mucosal formation of the cyclo‐oxygenase product, 6‐keto‐prostaglandin F1α, which was unaltered following ethanol challenge, was not inhibited by the acetohydroxamic acids. Likewise, the small increase in mucosal thromboxane B2 formation following challenge was not inhibited by BW A4C. Neither BW A4C nor BW A137C, at doses that almost completely inhibited the mucosal synthesis of LTB4 or LTC4, reduced the macroscopic gastric mucosal damage induced by ethanol. Pretreatment with the lipoxygenase inhibitor BW 755C (5–50 mg kg−1 p.o.) did reduce mucosal damage, but there was a dissociation between the degree of protection and the inhibition of leukotriene biosynthesis. Oral administration of high doses of either BW A4C or BW A137C (300 mg kg−1) did not induce macroscopic gastric damage over a 3 h period. These findings suggest that the leukotrienes, LTB4 and LTC4 are not the primary mediators of ethanol‐induced acute mucosal damage, but do not exclude their role in more chronic gastric damage and inflammation.

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Acetohydroxamic acids as potent, selective, orally active 5-lipoxygenase inhibitors

Cited by 58 publications

References 3 publications

Dual Acting Anti-Inflammatory Drugs

Dual Acting Anti-Inflammatory Drugs

Selective inhibition of arachidonate 5‐lipoxygenase by novel acetohydroxamic acids: effects on acute inflammatory responses

Failure of the inhibition of rat gastric mucosal 5‐lipoxygenase by novel acetohydroxamic acids to prevent ethanol‐induced damage

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