Abstract
The synthesis and structure-activity relationships (SAR) of a series of benzothiophene piperazine and piperidine urea FAAH inhibitors is described. These compounds inhibit FAAH by covalently modifying the enzyme's active site serine nucleophile. Activity-based protein profiling (ABPP) revealed that these urea inhibitors were completely selective for FAAH relative to other mammalian serine hydrolases. Several compounds showed in vivo activity in a rat complete Freund's adjuvant (CFA) model of inflammatory pain.
MeSH terms
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Amidohydrolases / antagonists & inhibitors*
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Amidohydrolases / metabolism
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Animals
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Computer Simulation
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Humans
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Models, Chemical
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Piperazines / chemical synthesis
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Piperazines / chemistry*
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Piperazines / pharmacology
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Piperidines / chemical synthesis
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Piperidines / chemistry*
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Piperidines / pharmacology
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Rats
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Structure-Activity Relationship
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Thiophenes / chemical synthesis
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Thiophenes / chemistry*
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Thiophenes / pharmacology
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Urea / analogs & derivatives*
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Urea / chemical synthesis
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Urea / pharmacology
Substances
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Enzyme Inhibitors
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Piperazines
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Piperidines
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Thiophenes
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benzothiophene
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Urea
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Amidohydrolases
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fatty-acid amide hydrolase