Determination of arachidonic acid by on-line solid-phase extraction HPLC with UV detection for screening of cytosolic phospholipase A2α inhibitors

Hanekamp, Walburga; Lehr, Matthias

doi:10.1016/j.jchromb.2012.05.018

Cited by 20 publications

(21 citation statements)

References 32 publications

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“…Another enzyme of the serine hydrolase family is cytosolic phospholipase A 2 α (cPLA 2 α), which catalyzes the first step of the so‐called arachidonic acid cascade by cleaving membrane phospholipids into arachidonic acid and lysophospholipids. At the highest test concentration of 10 μ m , cPLA 2 α was not inhibited by 32 and 59 . These results indicate that the inhibitors investigated display some specificity with regard to their ability to inhibit serine hydrolase enzymes.…”

Section: Resultsmentioning

confidence: 84%

“…Inhibition of cytosolic phospholipase A 2 α (cPLA 2 α) : Inhibition of cPLA 2 α was measured according to a recently published procedure . Briefly, cPLA 2 α isolated from porcine platelets was incubated with co‐vesicles consisting of the substrate 1‐stearoyl‐2‐arachidonoyl‐ sn ‐glycero‐3‐phosphocholine (200 μ m ) and 1,2‐dioleoyl‐ sn ‐glycerol (100 μ m ).…”

Section: Methodsmentioning

confidence: 99%

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ω‐Imidazolyl‐ and ω‐Tetrazolylalkylcarbamates as Inhibitors of Fatty Acid Amide Hydrolase: Biological Activity and in vitro Metabolic Stability

et al. 2016

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Fatty acid amide hydrolase (FAAH) is a serine hydrolase that terminates the analgesic and anti-inflammatory effects of endocannabinoids such as anandamide. Herein, structure-activity relationship studies on a new series of aryl N-(ω-imidazolyl- and ω-tetrazolylalkyl)carbamate inhibitors of FAAH were investigated. As one result, a pronounced increase in inhibitory potency was observed if a phenyl residue attached to the carbamate oxygen atom was replaced by a pyridin-3-yl moiety. The most active compounds exhibited IC50 values in the low nanomolar range. In addition, investigations on the metabolic properties of these inhibitors were performed. In rat liver homogenate and in porcine plasma, the extent of their degradation was shown to be strongly dependent on the kind of aryl residue bound to the carbamate as well as on the length and type of the alkyl spacer connecting the carbamate group with the heterocyclic system. With the aid of esterase inhibitors it was shown that in porcine plasma, carboxylesterase-like enzymes and paraoxonase are involved in carbamate cleavage. Moreover, it was found that highly active pyridin-3-yl carbamates reacted with albumin, which led to covalent albumin adducts.

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Section: Resultsmentioning

confidence: 84%

Section: Methodsmentioning

confidence: 99%

ω‐Imidazolyl‐ and ω‐Tetrazolylalkylcarbamates as Inhibitors of Fatty Acid Amide Hydrolase: Biological Activity and in vitro Metabolic Stability

et al. 2016

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“…Then di-tert-butyl dicarbonate (0.174 g, 0.80 mmol) was added and the mixture was stirred at room temperature for 2 h, concen-trated and chromatographed on silica gel (hexane-ethyl acetate, 9 : 1 to 6 : 4) to afford 19 as an oil (0.256 g, 97%). 1 (21). To a solution of 20 (2.25 g, 4.25 mmol) in CH 2 Cl 2 (40 mL) were added tetrabutylammonium hydrogen sulfate (0.231 g, 0.68 mmol) and freshly powdered potassium hydroxide (88%) (1.08 g, 17 mmol).…”

Section: Methodsmentioning

confidence: 99%

“…The target compounds were evaluated for cPLA 2 α inhibition in an assay using cPLA 2 α isolated from porcine platelets. 21 When measuring the inhibitory potency of 4, (S)-4 and (R)-4 it became evident that the data were strongly influenced by small impurities of the extreme potent indazolylpropan-2-one 3 (IC 50 : 0.0045 µM) present in the substances. The highest amounts of 3 (about 1% measured by HPLC/UV and MS) were found in 4 synthesized via the route shown in Scheme 1.…”

Section: Biological Evaluationmentioning

confidence: 99%

Convergent and enantioselective syntheses of cytosolic phospholipase A₂α inhibiting N-(1-indazol-1-ylpropan-2-yl)carbamates

et al. 2014

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Cytosolic phospholipase A2α (cPLA2α) is an important enzyme of the inflammation cascade. Therefore, inhibitors of cPLA2α are assumed to be promising drug candidates for the treatment of inflammatory disorders. Recently we have found that indole-5-carboxylic acid with a 3-(4-octylphenoxy)-2-(phenoxycarbonylamino)propyl substituent in position 1 is an inhibitor of cPLA2α. We have now synthesized a corresponding derivative with the indole heterocycle replaced by an indazole (4) employing an analogous reaction sequence as for the synthesis of the indole derivative. Besides, a more convergent synthesis for 4 was established using an aziridine as central intermediate. Furthermore, a chiral-pool based enantioselective synthesis was developed for the synthesis of (R)- and (S)-4. Starting compound for both enantiomers was the (R)-serine derived oxazolidine (R)-25. Compound 4 proved to be a moderate inhibitor of cPLA2α, with the S-enantiomer being twice as active as the R-enantiomer. The racemate 4 and the enantiomers (R)- and (S)-4 showed a high in vitro metabolic stability in rat liver S9 fractions.

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“…Inhibition of cPLA 2 a was measured according to a recently published procedure 24 . Briefly, cPLA 2 a isolated from porcine platelets was incubated with co-vesicles consisting of the substrate 1-stearoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (200 mM) and 1,2-dioleoyl-sn-glycerol (100 mM).…”

Section: Biological Evaluationmentioning

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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Determination of arachidonic acid by on-line solid-phase extraction HPLC with UV detection for screening of cytosolic phospholipase A2α inhibitors

Cited by 20 publications

References 32 publications

ω‐Imidazolyl‐ and ω‐Tetrazolylalkylcarbamates as Inhibitors of Fatty Acid Amide Hydrolase: Biological Activity and in vitro Metabolic Stability

ω‐Imidazolyl‐ and ω‐Tetrazolylalkylcarbamates as Inhibitors of Fatty Acid Amide Hydrolase: Biological Activity and in vitro Metabolic Stability

Convergent and enantioselective syntheses of cytosolic phospholipase A₂α inhibiting N-(1-indazol-1-ylpropan-2-yl)carbamates

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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Determination of arachidonic acid by on-line solid-phase extraction HPLC with UV detection for screening of cytosolic phospholipase A2α inhibitors

Cited by 20 publications

References 32 publications

ω‐Imidazolyl‐ and ω‐Tetrazolylalkylcarbamates as Inhibitors of Fatty Acid Amide Hydrolase: Biological Activity and in vitro Metabolic Stability

ω‐Imidazolyl‐ and ω‐Tetrazolylalkylcarbamates as Inhibitors of Fatty Acid Amide Hydrolase: Biological Activity and in vitro Metabolic Stability

Convergent and enantioselective syntheses of cytosolic phospholipase A2α inhibiting N-(1-indazol-1-ylpropan-2-yl)carbamates

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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Convergent and enantioselective syntheses of cytosolic phospholipase A₂α inhibiting N-(1-indazol-1-ylpropan-2-yl)carbamates

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