1-Indol-1-yl-propan-2-ones and related heterocyclic compounds as dual inhibitors of cytosolic phospholipase A2α and fatty acid amide hydrolase

Forster, Laura; Ludwig, Joachim; Kaptur, Martina; Bovens, Stefanie; Elfringhoff, Alwine Schulze; Holtfrerich, Angela; Lehr, Matthias

doi:10.1016/j.bmc.2009.11.028

Cited by 35 publications

(38 citation statements)

References 41 publications

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“…Compounds in this series are undergoing clinical trials for various inflammatory disorders. All of the other compounds studied are analogs of the original h-cPLA 2 ␣ inhibitor, arachidonyltrifluoromethyl ketone (27), and contain an electrophilic ketone group (15).…”

Section: Resultsmentioning

confidence: 99%

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Interfacial Kinetic and Binding Properties of Mammalian Group IVB Phospholipase A2 (cPLA2β) and Comparison with the Other cPLA2 Isoforms

Ghomashchi

Naika

Bollinger

et al. 2010

Journal of Biological Chemistry

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The cytosolic (group IV) phospholipase A 2 (cPLA 2 s) family contains six members. We have prepared recombinant proteins for human ␣, mouse ␤, human ␥, human ␦, human ⑀, and mouse cPLA 2 s and have studied their interfacial kinetic and binding properties in vitro. Mouse cPLA 2 ␤ action on phosphatidylcholine vesicles is activated by anionic phosphoinositides and cardiolipin but displays a requirement for Ca 2؉ only in the presence of cardiolipin. This activation pattern is explained by the effects of anionic phospholipids and Ca 2؉ on the interfacial binding of mouse cPLA 2 ␤ and its C2 domain to vesicles. Ca 2؉ -dependent binding of mouse cPLA 2 ␤ to cardiolipin-containing vesicles requires a patch of basic residues near the Ca 2؉ -binding surface loops of the C2 domain, but binding to phosphoinositide-containing vesicles does not depend on any specific cluster of basic residues. Human cPLA 2 ␦ also displays Ca 2؉ -and cardiolipin-enhanced interfacial binding and activity. The lysophospholipase, phospholipase A 1 , and phospholipase A 2 activities of the full set of mammalian cPLA 2 s were quantified. The relative level of these activities is very different among the isoforms, and human cPLA 2 ␦ stands out as having relatively high phospholipase A 1 activity. We also tested the susceptibility of all cPLA 2 family members to a panel of previously reported inhibitors of human cPLA 2 ␣ and analogs of these compounds. This led to the discovery of a potent and selective inhibitor of mouse cPLA 2 ␤. These in vitro studies help determine the regulation and function of the cPLA 2 family members.It is well established that cytosolic phospholipase A 2 -␣ (cPLA 2 ␣) 2 (also known as group IVA cPLA 2 ) liberates arachidonic acid from the sn-2 position of membrane phospholipids in agonist-stimulated mammalian cells for the biosynthesis of eicosanoids. With the completion of the mouse and human genomes, it became clear that these mammals also contain other proteins homologous to cPLA 2 ␣, namely the ␤, ␥, ␦, ⑀, and isoforms (groups IVB-F cPLA 2 s) (1, 2). This study is focused on the ␤ isoform of mouse cPLA 2 (m-cPLA 2 ␤) and its comparison with the other isoforms. m-cPLA 2 ␤ and cPLA 2 ␣ have a similar modular structure with an N-terminal C2 domain linked to a catalytic domain containing the active site serine involved in the lipolytic catalysis. Human cPLA 2 ␤ differs in that it contains an N-terminal truncated JmJc domain of unknown function followed by a C2 domain and a catalytic domain. Furthermore, human cPLA 2 ␤ exists as two splice forms, human cPLA 2 ␤1 and human cPLA 2 ␤3, with the latter being the major protein form expressed in a large variety of human tissues (3). The differential splicing leads to a change in a portion of the catalytic domain that is probably not part of the active site cleft. As far as we know, m-cPLA 2 ␤ exists as a single splice form (4). An intriguing property of m-cPLA 2 ␤, human cPLA 2 ␤1, and human cPLA 2 ␤3 is that they display specific activities for the hydrolysis of lysophosphatidylc...

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Section: Resultsmentioning

confidence: 99%

“…Wyeth-1 (also known as ecopladib), Wyeth-2 (also known as giripladib), Wyeth-3, pyrrolidine-1, and pyrrolidine-2 (also known as pyrrophenone) were prepared as described previously (11,12). The other inhibitors listed in supplemental Table 1 were prepared as described previously (13)(14)(15).…”

Section: Methodsmentioning

confidence: 99%

Interfacial Kinetic and Binding Properties of Mammalian Group IVB Phospholipase A2 (cPLA2β) and Comparison with the Other cPLA2 Isoforms

Ghomashchi

Naika

Bollinger

et al. 2010

Journal of Biological Chemistry

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“…In conclusion, continuing our work on similar substances, [28] we have found some more indol-1-ylpropan-2-ones and related heterocyclic compounds with dual cPLA 2 a and FAAH inhibitory [a] Values are the means of at least two independent determinations; errors are within AE 20 %.…”

Section: Discussionmentioning

confidence: 99%

1‐(3‐Biaryloxy‐2‐oxopropyl)indole‐5‐carboxylic Acids and Related Compounds as Dual Inhibitors of Human Cytosolic Phospholipase A₂α and Fatty Acid Amide Hydrolase

et al. 2011

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Cytosolic phospholipase A2α (cPLA2α) and fatty acid amide hydrolase (FAAH) are enzymes that have emerged as attractive targets for the development of analgesic and anti-inflammatory drugs. We recently reported that 1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid (5) is a dual inhibitor of cPLA2α and FAAH. Structure-activity relationship studies revealed that substituents at the indole 3- and 5-positions and replacement of the indole scaffold of this compound by other heterocycles strongly influences the inhibitory potency against cPLA2α and FAAH, respectively. Herein we report the effect of variation of the 4-octyl residue of 5 and an exchange of its carboxylic acid moiety by some bioisosteric functional groups. Several of the compounds assayed were favorably active against both enzymes, and could therefore represent agents with improved analgesic and anti-inflammatory qualities in comparison with selective cPLA2 α and FAAH inhibitors.

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“…1 H NMR spectra were recorded on an Agilent DD2 spectrometer (Agilent Technologies, Richardson, TX) (400 MHz) or an Agilent DD2 spectrometer (600 MHz). 13 C NMR spectra were measured on an Agilent DD2 spectrometer (Agilent Technologies, Richardson, TX) (101 MHz) or an Agilent DD2 spectrometer (151 MHz). Electron ionization (EI) mass spectra were obtained on a Finnigan GCQ apparatus (Finnigan Corporation, San Jose, CA).…”

Section: Generalmentioning

confidence: 99%

Structure–activity relationship studies on 1-heteroaryl-3-phenoxypropan-2-ones acting as inhibitors of cytosolic phospholipase A₂αand fatty acid amide hydrolase: replacement of the activated ketone group by other serine traps

Sundermann

Hanekamp

Lehr

2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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Structure-activity relationship studies on 1-heteroaryl-3-phenoxypropan-2-ones acting as inhibitors of cytosolic phospholipase A 2 α and fatty acid amide hydrolase: replacement of the activated ketone group by other serine traps, Journal AbstractCytosolic phospholipase A 2 a (cPLA 2 a) and fatty acid amide hydrolase (FAAH) are serine hydrolases. cPLA 2 a is involved in the generation of pro-inflammatory lipid mediators, FAAH terminates the anti-inflammatory effects of endocannabinoids. Therefore, inhibitors of these enzymes may represent new drug candidates for the treatment of inflammation. We have reported that certain 1-heteroarylpropan-2-ones are potent inhibitors of cPLA 2 a and FAAH. The serine reactive ketone group of these compounds, which is crucial for enzyme inhibition, is readily metabolized resulting in inactive alcohol derivatives. In order to obtain metabolically more stable inhibitors, we replaced this moiety by a-ketoheterocyle, cyanamide and nitrile serine traps. Investigations on activity and metabolic stability of these substances revealed that in all cases an increased metabolic stability was accompanied by a loss of inhibitory potency against cPLA 2 a and FAAH, respectively. KeywordsCytosolic phospholipase A 2 a, fatty acid amide hydrolase, inhibitor, metabolic stability, serine trap History

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1-Indol-1-yl-propan-2-ones and related heterocyclic compounds as dual inhibitors of cytosolic phospholipase A2α and fatty acid amide hydrolase

Cited by 35 publications

References 41 publications

Interfacial Kinetic and Binding Properties of Mammalian Group IVB Phospholipase A2 (cPLA2β) and Comparison with the Other cPLA2 Isoforms

Interfacial Kinetic and Binding Properties of Mammalian Group IVB Phospholipase A2 (cPLA2β) and Comparison with the Other cPLA2 Isoforms

1‐(3‐Biaryloxy‐2‐oxopropyl)indole‐5‐carboxylic Acids and Related Compounds as Dual Inhibitors of Human Cytosolic Phospholipase A₂α and Fatty Acid Amide Hydrolase

Structure–activity relationship studies on 1-heteroaryl-3-phenoxypropan-2-ones acting as inhibitors of cytosolic phospholipase A₂αand fatty acid amide hydrolase: replacement of the activated ketone group by other serine traps

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1-Indol-1-yl-propan-2-ones and related heterocyclic compounds as dual inhibitors of cytosolic phospholipase A2α and fatty acid amide hydrolase

Cited by 35 publications

References 41 publications

Interfacial Kinetic and Binding Properties of Mammalian Group IVB Phospholipase A2 (cPLA2β) and Comparison with the Other cPLA2 Isoforms

Interfacial Kinetic and Binding Properties of Mammalian Group IVB Phospholipase A2 (cPLA2β) and Comparison with the Other cPLA2 Isoforms

1‐(3‐Biaryloxy‐2‐oxopropyl)indole‐5‐carboxylic Acids and Related Compounds as Dual Inhibitors of Human Cytosolic Phospholipase A2α and Fatty Acid Amide Hydrolase

Structure–activity relationship studies on 1-heteroaryl-3-phenoxypropan-2-ones acting as inhibitors of cytosolic phospholipase A2αand fatty acid amide hydrolase: replacement of the activated ketone group by other serine traps

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1‐(3‐Biaryloxy‐2‐oxopropyl)indole‐5‐carboxylic Acids and Related Compounds as Dual Inhibitors of Human Cytosolic Phospholipase A₂α and Fatty Acid Amide Hydrolase

Structure–activity relationship studies on 1-heteroaryl-3-phenoxypropan-2-ones acting as inhibitors of cytosolic phospholipase A₂αand fatty acid amide hydrolase: replacement of the activated ketone group by other serine traps