Abstract
1,3-Disubstituted ureas possessing a piperidyl moiety have been synthesized to investigate their structure-activity relationships as inhibitors of the human and murine soluble epoxide hydrolase (sEH). Oral administration of 13 1-aryl-3-(1-acylpiperidin-4-yl)urea inhibitors in mice revealed substantial improvements in pharmacokinetic parameters over previously reported 1-adamantylurea based inhibitors. For example, 1-(1-(cyclopropanecarbonyl)piperidin-4-yl)-3-(4-(trifluoromethoxy)phenyl)urea (52) showed a 7-fold increase in potency, a 65-fold increase in C(max), and a 3300-fold increase in AUC over its adamantane analogue 1-(1-adamantyl)-3-(1-propionylpiperidin-4-yl)urea (2). This novel sEH inhibitor showed a 1000-fold increase in potency when compared to morphine by reducing hyperalgesia as measured by mechanical withdrawal threshold using the in vivo carrageenan induced inflammatory pain model.
Publication types
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Comparative Study
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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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Adamantane / analogs & derivatives
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Adamantane / chemical synthesis
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Adamantane / pharmacokinetics
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Adamantane / pharmacology
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Analgesics, Opioid / pharmacology
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
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Anti-Inflammatory Agents, Non-Steroidal / pharmacokinetics
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Carrageenan
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Epoxide Hydrolases / antagonists & inhibitors*
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Humans
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Male
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Mice
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Morphine / pharmacology
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Pain / chemically induced
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Pain / drug therapy*
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Piperidines / chemical synthesis*
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Piperidines / pharmacokinetics
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Piperidines / pharmacology
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Rats
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Rats, Sprague-Dawley
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Solubility
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Structure-Activity Relationship
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Urea / analogs & derivatives*
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Urea / chemical synthesis*
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Urea / pharmacokinetics
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Urea / pharmacology
Substances
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Analgesics, Opioid
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Anti-Inflammatory Agents, Non-Steroidal
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Piperidines
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Morphine
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Urea
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Carrageenan
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Epoxide Hydrolases
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Adamantane