Anti-inflammatory activities of LDP-392, A dual PAF receptor antagonist and 5-lipoxygenase inhibitor

doi:10.1006/phrs.2001.0808

Pharmacological Research

Volume 44, Issue 3, September 2001, Pages 213-220

https://doi.org/10.1006/phrs.2001.0808 Get rights and content

Abstract

Leukotrienes (LTs) and platelet-activating factor (PAF) are important mediators of inflammation and allergy. LDP-392, a novel dual PAF receptor antagonist and 5-lipoxygenase (5-LO) inhibitor, has been identified. LDP-392 is 17.9-fold more potent than zileuton (5-LO inhibitor) in the RBL cytosolic 5-LO assay, and equally potent as MK 287 (PAF receptor antagonist) in the human platelet PAF receptor binding assay. The in vivo dual activities of LDP-392 were confirmed by measuring the inhibition of ex vivo LTB₄production in rats and PAF-induced hemoconcentration in mice. Intravenous administration of LDP-392 demonstrated greater inhibition than zileuton, BN 50739 or MK 287 on arachidonic acid-induced ear edema and protected mice from LPS-induced lethality. Topical administration of LDP-392, in a dose-dependent manner, inhibited TPA-induced ear edema in mice and UVB-induced erythema in guinea-pigs. These data suggest that LDP-392, as a dual PAF receptor antagonist and 5-LO inhibitor, may be of greater clinical effectiveness.

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Citation Excerpt :
For example, rupatadine, which blocks both PAF-R and histamine receptor H1[[31]], has been used in symptomatic allergic rhinitis [32,33]. Similarly, LDP-392, which inhibits both 5-lipoxygenase and PAF-R, has been used against LPS-induced lethality [34]. The popular cholesterol-lowering drug simvastatin appears to exhibit decreased biosynthesis of PAF in isolated cells of human volunteers [35].
Platelet-activating factor (PAF), a bioactive ether phospholipid with significant pro-inflammatory properties, was identified almost half a century ago. Despite extensive study of this autocoid, therapeutic strategies for targeting its signaling components have not been successful, including the recent clinical trials with darapladib, a drug that targets plasma PAF-acetylhydrolase (PAF-AH). We recently provided experimental evidence that the previously unrecognized acyl analog of PAF, which is concomitantly produced along with PAF during biosynthesis, dampens PAF signaling by acting both as a sacrificial substrate for PAF-AH and probably as an endogenous PAF-receptor antagonist/partial agonist. If this is the scenario in vivo, PAF-AH needs to catalyze the selective hydrolysis of alkyl-PAF and not acyl-PAF. Accordingly, different approaches are needed for treating inflammatory diseases in which PAF signaling is implicated. The interplay between acyl-PAF, alkyl-PAF, PAF-AH, and PAF-R is complex, and the outcome of this interplay has not been previously appreciated. In this review, we discuss this interaction based on our recent findings. It is very likely that the relative abundance of acyl and alkyl-PAF and their interactions with PAF-R in the presence of their hydrolyzing enzyme PAF-AH may exert a modulatory effect on PAF signaling during inflammation.
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5-Lipoxygenase (5-LO) catalyzes the conversion of arachidonic acid (AA) into leukotriene (LT) A₄ and 5-hydroperoxyeicosatetraenoic acid. LTA₄ can then be converted into LTB₄ by LTA₄ hydrolase or into LTC₄ by LTC₄ synthase and the LTC₄ synthase isoenzymes MGST2 and MGST3. LTB₄ is a potent chemoattractant for neutrophils, eosinophils and monocytes leading to adherence of phagocytes to vessel walls, neutrophil degranulation and release of superoxide anions. LTC₄ and its metabolite, LTD₄, are potent bronchoconstrictors that increase vascular permeability and stimulate mucus secretion from airways. Recent data also suggest that LT have an immunomodulatory role. Due to these properties, the increased biosynthesis of LT in asthma, and based upon clinical data obtained with CysLT₁ receptor antagonists in asthma patients, there is a consensus that CysLT play a prominent role in asthma. In this review, we summarize the knowledge on possible functions of the 5-LO pathway in various diseases like asthma, cancer and cardiovascular events and review the corresponding potential therapeutic roles of 5-LO inhibitors.
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¹: Corresponding author. Millennium Pharmaceutical Inc., 75 Sidney Street, Cambridge, MA 02139, [email protected]

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Regular ArticleAnti-inflammatory activities of LDP-392, A dual PAF receptor antagonist and 5-lipoxygenase inhibitor

Abstract

J Allergy Clin Immunol

Blood

Prostaglandins Leukot Essent Fatty Acids

Prostaglandins

Respir Physiol

Prostaglandins Leukot Essent Fatty Acids

Lancet

J Allergy Clin Immunol

J Allergy Clin Immunol

Biochem Pharmacol

J Biol Chem

J Invest Dermatol

J Invest Dermatol

Eur J Pharmacol

Platelet-activating factor and related acetylated lipids as potent biologically active cellular mediators

Am J Physiol

Platelet activating factor (PAF). A review of its effects, antagonists and possible future clinical implications (Part I)

Drugs

Comparison differences and combined effects of interleukin-8, leukotriene B4, and platelet-activating factor on neutrophil chemotaxis of the newborn

Pediatr Res

Preferential human eosinophil chemotactic activity of the platelet-activating factor (PAF) 1-0-hexadecyl-2-acetyl-sn-glyceryl-3-phosphocholine (AGEPC)

J Clin Immunol

Platelet-activating factor. A potent chemotactic and chemokinetic factor for human eosinophils

J Clin Invest

Eosinophil chemotaxis inhibited by 5-lipoxygenase blockade and leukotriene receptor antagonism

Am J Respir Crit Care Med

Increased monocyte chemotaxis towards leukotriene B4 and platelet activating factor in patients with inflammatory dermatoses

Clin Exp Immunol

Reversal of leukotriene D4- and leukotriene E4-induced airway constriction in the Guinea-pig

Am Rev Respir Dis

Platelet-activating factor is a key mediator of pulmonary vasoconstriction and bronchoconstriction after antigen challenge in the perfused sensitized rabbit lung

Shock

Paf-acether (platelet-activating factor) increases microvascular permeability and affects endothelium granulocyte interaction in microvascular beds

Acta Physiol Scand

Leukotriene B4: a mediator of vascular permeability

Br J Pharmacol

Effects of PAF antagonists in mouse ear oedema induced by several inflammatory agents

Br J Pharmacol

Regular Article
Anti-inflammatory activities of LDP-392, A dual PAF receptor antagonist and 5-lipoxygenase inhibitor

Reversal of leukotriene D₄- and leukotriene E₄-induced airway constriction in the Guinea-pig