(4-Phenoxyphenyl)tetrazolecarboxamides and related compounds as dual inhibitors of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL)

Holtfrerich, Angela; Hanekamp, Walburga; Lehr, Matthias

doi:10.1016/j.ejmech.2013.01.050

Cited by 30 publications

(44 citation statements)

References 51 publications

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“…The reaction occurs under very mild conditions (0 o C→20 o C) over 0. [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24], has excellent functional group tolerance and proceeds whether the amide group is at C (3) or C(4) of the furoxan ring. For the preparation of cyanofuroxans 1a,b,f,i (Table 1, entries 1,2,6,9), dry…”

Section: Mmentioning

confidence: 99%

An efficient access to (1H-tetrazol-5-yl)furoxan ammonium salts via a two-step dehydration/[3+2]-cycloaddition strategy

et al. 2015

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Section: Mmentioning

confidence: 99%

An efficient access to (1H-tetrazol-5-yl)furoxan ammonium salts via a two-step dehydration/[3+2]-cycloaddition strategy

et al. 2015

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“…The carbamate derivatives prepared in this study were tested for their ability to inhibit FAAH from rat brain by monitoring cleavage of a fluorogenic substrate by HPLC fluorescence detection as previously described …”

Section: Resultsmentioning

confidence: 99%

“…Inhibition of FAAH : Inhibition of FAAH was measured with FAAH as described . Briefly, the substrate N ‐(2‐hydroxyethyl)‐4‐pyren‐1‐ylbutanamide (100 μ m ) solubilized with Triton X‐100 (0.2 %) was incubated with rat brain microsomes.…”

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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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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“…The metabolic stability was tested using S9 fractions of rat liver homogenate 25 . Briefly, the test compounds were incubated under aerobic conditions in the absence and presence of the co-factor NADPH.…”

Section: Metabolic Stability In Rat Liver S9 Fractionsmentioning

confidence: 99%

“…Inhibition of FAAH was measured as described 25 . Briefly, the substrate N-(2-hydroxyethyl)-4-pyren-1-ylbutanamide 26 (100 mM) solubilized with Triton X-100 (0.2 %) was incubated with rat brain microsomes.…”

Section: Inhibition Of Fatty Acid Amide Hydrolase (Faah)mentioning

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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(4-Phenoxyphenyl)tetrazolecarboxamides and related compounds as dual inhibitors of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL)

Cited by 30 publications

References 51 publications

An efficient access to (1H-tetrazol-5-yl)furoxan ammonium salts via a two-step dehydration/[3+2]-cycloaddition strategy

An efficient access to (1H-tetrazol-5-yl)furoxan ammonium salts via a two-step dehydration/[3+2]-cycloaddition strategy

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

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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(4-Phenoxyphenyl)tetrazolecarboxamides and related compounds as dual inhibitors of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL)

Cited by 30 publications

References 51 publications

An efficient access to (1H-tetrazol-5-yl)furoxan ammonium salts via a two-step dehydration/[3+2]-cycloaddition strategy

An efficient access to (1H-tetrazol-5-yl)furoxan ammonium salts via a two-step dehydration/[3+2]-cycloaddition strategy

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

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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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