Abstract
Inspired by previously discovered enhanced analgesic efficacy between soluble epoxide hydrolase (sEH) and phosphodiesterase 4 (PDE4) inhibitors, we designed, synthesized and characterized 21 novel sEH/PDE4 dual inhibitors. The best of these displayed good efficacy in in vitro assays. Further pharmacokinetic studies of a subset of four selected compounds led to the identification of a bioavailable dual inhibitor N-(4-methoxy-2-(trifluoromethyl)benzyl)-1-propionylpiperidine-4-carboxamide (MPPA). In a lipopolysaccharide induced inflammatory pain rat model, MPPA rapidly increased in the blood ( Tmax = 30 min; Cmax = 460 nM) after oral administration of 3 mg/kg and reduced inflammatory pain with rapid onset of action correlating with blood levels over a time course of 4 h. Additionally, MPPA does not alter self-motivated exploration of rats with inflammatory pain or the withdrawal latency in control rats.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Oral
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Analgesics / administration & dosage
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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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Epoxide Hydrolases / antagonists & inhibitors*
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HEK293 Cells
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Humans
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Inflammation / chemically induced
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Inflammation / complications
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Lipopolysaccharides
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Male
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Molecular Structure
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Pain / drug therapy*
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Pain / etiology
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Phosphodiesterase 4 Inhibitors / administration & dosage
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Phosphodiesterase 4 Inhibitors / chemical synthesis
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Phosphodiesterase 4 Inhibitors / pharmacokinetics
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Phosphodiesterase 4 Inhibitors / therapeutic use*
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Piperidines / administration & dosage
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Piperidines / chemical synthesis
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Piperidines / pharmacokinetics
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Piperidines / therapeutic use*
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Rats, Sprague-Dawley
Substances
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Analgesics
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Lipopolysaccharides
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Phosphodiesterase 4 Inhibitors
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Piperidines
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Epoxide Hydrolases
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EPHX2 protein, human
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EPHX2 protein, rat
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Ephx2 protein, mouse