Abstract
A series of piperazine ureas were designed, synthesized, and evaluated for their potential as novel orally efficacious fatty acid amide hydrolase (FAAH) inhibitors for the treatment of neuropathic and inflammatory pain. We carried out an optimization study of compound 5 to improve its in vitro FAAH inhibitory activity, and identified the 2-pyrimidinylpiperazine derivative 21d with potent inhibitory activity, favorable DMPK profile and brain permeability. Compound 21d showed robust and dose-dependent analgesic efficacy in animal models of both neuropathic and inflammatory pain.
Keywords:
Arachidonoylethanolamide; Fatty acid amide hydrolase inhibitors; Inflammatory pain; Neuropathic pain; Piperazine ureas.
Copyright © 2014. Published by Elsevier Ltd.
MeSH terms
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Administration, Oral
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Amidohydrolases / antagonists & inhibitors*
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Amidohydrolases / metabolism
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Analgesics / chemical synthesis*
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Analgesics / pharmacokinetics
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Analgesics / therapeutic use
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Animals
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Brain / metabolism
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Disease Models, Animal
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Drug Design*
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / pharmacokinetics
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Enzyme Inhibitors / therapeutic use
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Half-Life
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Male
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Mice
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Mice, Inbred ICR
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Pain / drug therapy
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Piperazine
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Piperazines / chemistry*
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Pyridazines / chemical synthesis*
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Pyridazines / pharmacokinetics
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Pyridazines / therapeutic use
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Pyrimidines / chemical synthesis*
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Pyrimidines / pharmacokinetics
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Pyrimidines / therapeutic use
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Rats
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Rats, Sprague-Dawley
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Urea / analogs & derivatives*
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Urea / pharmacokinetics
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Urea / therapeutic use
Substances
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4-(4-(3,4-difluorophenyl)pyrimidin-2-yl)-N-(pyridazin-3-yl)piperazine-1-carboxamide
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Analgesics
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Enzyme Inhibitors
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Piperazines
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Pyridazines
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Pyrimidines
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Piperazine
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Urea
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Amidohydrolases
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fatty-acid amide hydrolase