Structure—Activity Relationship Studies of 1‐Substituted 3‐Dodecanoylindole‐2‐carboxylic Acids as Inhibitors of Cytosolic Phospholipase A<sub>2</sub>‐Mediated Arachidonic Acid Release in Intact Platelets.

Griessbach, Klaus; Klimt, Monika; Elfringhoff, Alwine Schulze; Lehr, Matthias

doi:10.1002/chin.200323215

Cited by 3 publications

(4 citation statements)

References 8 publications

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“…ML3176, which is also characterized as a specific inhibitor for cytosolic PLA 2 [176], showed to inhibit partially the overall Ca 2+ -dependent PLA 2 activity detected in BAL fluid, BAL cells and plasma of ARDS patients suggesting that cPLA 2 might participate in regulation of inflammation in ARDS.…”

Section: Accepted Manuscriptmentioning

confidence: 96%

Phospholipase A2 subclasses in acute respiratory distress syndrome

Kitsiouli

Nakos

Lekka

2009

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Phospholipases A2 (PLA2) catalyse the cleavage of fatty acids esterified at the sn-2 position of glycerophospholipids. In acute lung injury-acute respiratory distress syndrome (ALI-ARDS) several distinct isoenzymes appear in lung cells and fluid. Some are capable to trigger molecular events leading to enhanced inflammation and lung damage and others have a role in lung surfactant recycling preserving lung function: Secreted forms (groups sPLA2-IIA, -V, -X) can directly hydrolyze surfactant phospholipids. Cytosolic PLA2 (cPLA2-IVA) requiring Ca2+ has a preference for arachidonate, the precursor of eicosanoids which participate in the inflammatory response in the lung. Ca(2+)-independent intracellular PLA2s (iPLA2) take part in surfactant phospholipids turnover within alveolar cells. Acidic Ca(2+)-independent PLA2 (aiPLA2), of lysosomal origin, has additionally antioxidant properties, (peroxiredoxin VI activity), and participates in the formation of dipalmitoyl-phosphatidylcholine in lung surfactant. PAF-AH degrades PAF, a potent mediator of inflammation, and oxidatively fragmented phospholipids but also leads to toxic metabolites. Therefore, the regulation of PLA2 isoforms could be a valuable approach for ARDS treatment.

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Section: Accepted Manuscriptmentioning

confidence: 96%

Phospholipase A2 subclasses in acute respiratory distress syndrome

Kitsiouli

Nakos

Lekka

2009

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…Several classes of cPLA 2 α inhibitors have been reported in the literature, and recently, reviews by Lehr and Kokotos have been published. Seno and co-workers at Shionogi have reported a class of pyrrolidine inhibitors represented in Chart by compound 1 . , Indole inhibitors with a C2 carboxylic acid (e.g., 2 ) have been reported by Lehr and co-workers. ,, Propanone inhibitors (e.g., 4 ) have been described by Connolly and co-workers . Dennis and co-workers have reported 2-oxoamide inhibitors represented by compound 5 and showed efficacy in the rat carrageenan-induced edema assay with intraperitoneal dosing and in models of pain with intrathecal dosing .…”

Section: Introductionmentioning

confidence: 98%

“…28,29 Indole inhibitors with a C2 carboxylic acid (e.g., 2) have been reported by Lehr and co-workers. 30,31,32 Propanone inhibitors (e.g., 4) have been described by Connolly and co-workers. 33 Dennis and co-workers have reported 2-oxoamide inhibitors represented by compound 5 34 and showed efficacy in the rat carrageenan-induced edema assay with intraperitoneal dosing 35 and in models of pain with intrathecal dosing.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Ecopladib, an Indole Inhibitor of Cytosolic Phospholipase Α₂α

Lee¹,

Foley²,

Chen³

et al. 2007

J. Med. Chem.

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The synthesis and structure-activity relationship of a series of indole inhibitors of cytosolic phospholipase A2alpha (cPLA2alpha, type IVA phospholipase) are described. Inhibitors of cPLA2alpha are predicted to be efficacious in treating asthma as well as the signs and symptoms of osteoarthritis, rheumatoid arthritis, and pain. The introduction of a benzyl sulfonamide substituent at C2 was found to impart improved potency of these inhibitors, and the SAR of these sulfonamide analogues is disclosed. Compound 123 (Ecopladib) is a sub-micromolar inhibitor of cPLA2alpha in the GLU micelle and rat whole blood assays. Compound 123 displayed oral efficacy in the rat carrageenan air pouch and rat carrageenan-induced paw edema models.

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“…64 These inhibitors range from electrophilic ketones, such as the trifluoromethyl ketone of arachdonic acid, [65][66][67][68][69] to natural products 70,71 that inhibit cPLA 2 R, to compounds that are purported to have dual 72 cPLA 2 R and sPLA 2 activity. Merckle [73][74][75] disclosed one of the first series of compounds thought to be inhibitors of cPLA 2 R. Elan 76 has patented a group of cPLA 2 R inhibitors generated from pyrimidones. Shionogi [77][78][79][80] has reported on a series of pyrrolidine-based inhibitors that are among the most potent cPLA 2 R inhibitors disclosed.…”

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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Structure—Activity Relationship Studies of 1‐Substituted 3‐Dodecanoylindole‐2‐carboxylic Acids as Inhibitors of Cytosolic Phospholipase A₂‐Mediated Arachidonic Acid Release in Intact Platelets.

Cited by 3 publications

References 8 publications

Phospholipase A2 subclasses in acute respiratory distress syndrome

Phospholipase A2 subclasses in acute respiratory distress syndrome

Discovery of Ecopladib, an Indole Inhibitor of Cytosolic Phospholipase Α₂α

Inhibition of Cytosolic Phospholipase A₂α: Hit to Lead Optimization

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Structure—Activity Relationship Studies of 1‐Substituted 3‐Dodecanoylindole‐2‐carboxylic Acids as Inhibitors of Cytosolic Phospholipase A2‐Mediated Arachidonic Acid Release in Intact Platelets.

Cited by 3 publications

References 8 publications

Phospholipase A2 subclasses in acute respiratory distress syndrome

Phospholipase A2 subclasses in acute respiratory distress syndrome

Discovery of Ecopladib, an Indole Inhibitor of Cytosolic Phospholipase Α2α

Inhibition of Cytosolic Phospholipase A2α: Hit to Lead Optimization

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Product

Resources

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Structure—Activity Relationship Studies of 1‐Substituted 3‐Dodecanoylindole‐2‐carboxylic Acids as Inhibitors of Cytosolic Phospholipase A₂‐Mediated Arachidonic Acid Release in Intact Platelets.

Discovery of Ecopladib, an Indole Inhibitor of Cytosolic Phospholipase Α₂α

Inhibition of Cytosolic Phospholipase A₂α: Hit to Lead Optimization