Platelet-activating factor and leukotriene biosynthesis is inhibited in polymorphonuclear leukocytes depleted of arachidonic acid.

Ramesha, Chakkodabylu S.; Pickett, Walter C.

doi:10.1016/s0021-9258(19)57436-1

Cited by 122 publications

(63 citation statements)

References 15 publications

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“…The pathway is of interest because metabolism of arachidonic acid (AA) a Abbreviations: cPLA 2 α, cytosolic phospholipase A 2 α; AA, arachidonic acid; PGs, prostaglandins; TXs, thromboxanes; LTs, leukotrienes; PAF, platelet activating factor; NSAIDs, nonsteroidal anti-inflammatory drugs; COX-2, cyclooxygenase-2; LTC 4 , D 4 , and E 4 , cysteinyl leukotrienes; ARDS, adult respiratory distress syndrome; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; APC, adenoma polyposis carcinoma; EAE, experimental autoimmune encephalomyelitis; GLU, 7-hydroxycoumarinyl-γ-linolenate; A23187, a calcium ionophore; COX-1, cyclooxygenase-1; 5-LO, 5-lipoxygenase; ITC, isothermal titration calorimetry; PAPC, 1-palmitoyl-2-arachidonoyl- sn -glycero-3-phosphocholine; PAPE, 1-palmitoyl-2-arachidonoyl- sn -glycero-3-phosphoethanolamine; sPLA 2 , type II secreted phospholipase A 2 ; TMPD, N , N , N ′, N ′-tetramethylbenzene-1,4-diamine; F , oral bioavailability; CPE carrageenan paw edema; CIA, collagen-induced arthritis; AIA, adjuvant-induced arthritis; AHR, acute hyperresponsiveness; LAR, late asthmatic response; FT-ICR, Fourier transform ion cyclotron resonance; ESI, electrospray ionization. produces multiple mediators of inflammation including prostaglandins (PGs), thromboxanes (TXs) and leukotrienes (LTs). Platelet activating factor (PAF), another inflammatory mediator, can be formed from the lysophospholipid that is produced in the cleavage of membrane phospholipids by cPLA 2 α to release AA. – Each of these mediators has been implicated in a variety of disease states. Nonsteroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase-2 (COX-2) inhibitors block the conversion of AA to PGs, and extensive clinical trials have confirmed that PGs are proinflammatory and potentiate pain .…”

Section: Introductionmentioning

confidence: 99%

Indole Cytosolic Phospholipase A₂ α Inhibitors: Discovery and in Vitro and in Vivo Characterization of 4-{3-[5-Chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1-(diphenylmethyl)-1H-indol-3-yl]propyl}benzoic Acid, Efipladib

et al. 2008

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The optimization of a class of indole cPLA 2 alpha inhibitors is described herein. The importance of the substituent at C3 and the substitution pattern of the phenylmethane sulfonamide region are highlighted. Optimization of these regions led to the discovery of 111 (efipladib) and 121 (WAY-196025), which are shown to be potent, selective inhibitors of cPLA 2 alpha in a variety of isolated enzyme assays, cell based assays, and rat and human whole blood assays. The binding of these compounds has been further examined using isothermal titration calorimetry. Finally, these compounds have shown efficacy when dosed orally in multiple acute and chronic prostaglandin and leukotriene dependent in vivo models.

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Section: Introductionmentioning

confidence: 99%

Indole Cytosolic Phospholipase A₂ α Inhibitors: Discovery and in Vitro and in Vivo Characterization of 4-{3-[5-Chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1-(diphenylmethyl)-1H-indol-3-yl]propyl}benzoic Acid, Efipladib

et al. 2008

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“…The third class of lipid mediator generated following AA release is platelet activating factor (PAF). Although the lysophospholipid precursor for PAF could be generated from phospholipids containing other fatty acids in the sn-2 position, the release of AA and PAF synthesis are linked. − Although PAF receptor antagonists have not been successful in the clinic, genetically altered mice either overexpressing or deficient in the PAF receptor support a role for PAF in inflammation . The effect of PAF may be difficult to antagonize, because inflamed endothelial cells synthesize and retain PAF at the cell surface, where it activates leukocytes in cooperation with other cell−cell interactions .…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Cytosolic Phospholipase A₂α: Hit to Lead Optimization

et al. 2005

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Compound 1 was previously reported to be a potent inhibitor of cPLA(2)alpha in both artificial monomeric substrate and cell-based assays. However, 1 was inactive in whole blood assays previously used to characterize cyclooxygenase and lipoxygenase inhibitors. The IC(50) of 1 increased dramatically with cell number or lipid/detergent concentration. In an attempt to insert an electrophilic ketone between the indole and benzoic acid moieties, we discovered that increasing the distance between the two moieties gave a compound with activity in the GLU (7-hydroxycoumarinyl-gamma-linolenate) micelle assay, which contains lipid and detergent. Extensive structure-activity relationship work around this lead identified a potent pharmacophore for cPLA(2)alpha inhibition. The IC(50)s between the GLU micelle and rat whole blood assays correlated highly. No correlation was found for other parameters, including lipophilicity or acidity of the required acid functionality. Compounds 25, 39, and 94 emerged as potent, selective inhibitors of cPLA(2)alpha and represent well-validated starting points for further optimization.

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“…Tissue arachidonic acid (C20:4 n-6) is derived mainly from dietary linoleic acid (C18:2 n-6) and is converted into eicosanoids such as prostaglandins and leukotrienes, which act as mediators of inflammation. EPA and DHA are preferred substrates for 5-lipoxygenase as compared with AA; therefore, the substitution of linoleic acid in diets with other PUFAs, such as EPA and DHA, is expected to attenuate inflammatory responses by reducing AA content or inhibiting eicosanoid generation and PAF biosynthesis (5).…”

Section: Introductionmentioning

confidence: 99%

Fatty Acid Composition and Antioxidant Levels in Muscle Tissue of Different Mediterranean Marine Species of Fish and Shellfish

Passi

Cataudella

Marco

et al. 2002

J. Agric. Food Chem.

141

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The levels of hydrophilic, lipophilic, and enzymatic antioxidants, as well as the fatty acids composition, of triglyceride and phospholipid fractions were determined in the muscle tissue of 21 species of teleosts, 3 species of cephalopods, and 6 species of crustaceans, just caught from the central Tyrrhenian Sea (Mediterranean Sea). The enzymatic activities and the levels of low-molecular-weight antioxidants, and the percentages of fatty acids, showed marked interspecies differences. Our results showed that total polyunsaturated fatty acids (21.7-61.5%) were the highest, followed by saturated (16.9-41.3%) and monounsaturated (9.1-42.8%) fatty acids. The total n-3 fatty acids content (16.6-57.1%) was found to be higher than the total n-6 fatty acids content (4.1-10.6%). All of the species studied had an n-3/n-6 ratio of more than 1, confirming the great importance of fish and shellfish as a significant dietary source of n-3 polyunsaturated fatty acids and their beneficial role in the Mediterranean type of diet.

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Platelet-activating factor and leukotriene biosynthesis is inhibited in polymorphonuclear leukocytes depleted of arachidonic acid.

Cited by 122 publications

References 15 publications

Indole Cytosolic Phospholipase A₂ α Inhibitors: Discovery and in Vitro and in Vivo Characterization of 4-{3-[5-Chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1-(diphenylmethyl)-1H-indol-3-yl]propyl}benzoic Acid, Efipladib

Indole Cytosolic Phospholipase A₂ α Inhibitors: Discovery and in Vitro and in Vivo Characterization of 4-{3-[5-Chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1-(diphenylmethyl)-1H-indol-3-yl]propyl}benzoic Acid, Efipladib

Inhibition of Cytosolic Phospholipase A₂α: Hit to Lead Optimization

Fatty Acid Composition and Antioxidant Levels in Muscle Tissue of Different Mediterranean Marine Species of Fish and Shellfish

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Platelet-activating factor and leukotriene biosynthesis is inhibited in polymorphonuclear leukocytes depleted of arachidonic acid.

Cited by 122 publications

References 15 publications

Indole Cytosolic Phospholipase A2 α Inhibitors: Discovery and in Vitro and in Vivo Characterization of 4-{3-[5-Chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1-(diphenylmethyl)-1H-indol-3-yl]propyl}benzoic Acid, Efipladib

Indole Cytosolic Phospholipase A2 α Inhibitors: Discovery and in Vitro and in Vivo Characterization of 4-{3-[5-Chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1-(diphenylmethyl)-1H-indol-3-yl]propyl}benzoic Acid, Efipladib

Inhibition of Cytosolic Phospholipase A2α: Hit to Lead Optimization

Fatty Acid Composition and Antioxidant Levels in Muscle Tissue of Different Mediterranean Marine Species of Fish and Shellfish

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About

Indole Cytosolic Phospholipase A₂ α Inhibitors: Discovery and in Vitro and in Vivo Characterization of 4-{3-[5-Chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1-(diphenylmethyl)-1H-indol-3-yl]propyl}benzoic Acid, Efipladib

Indole Cytosolic Phospholipase A₂ α Inhibitors: Discovery and in Vitro and in Vivo Characterization of 4-{3-[5-Chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1-(diphenylmethyl)-1H-indol-3-yl]propyl}benzoic Acid, Efipladib

Inhibition of Cytosolic Phospholipase A₂α: Hit to Lead Optimization