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.
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Authors | Tristan E Rose, Christophe Morisseau, Jun-Yan Liu, Bora Inceoglu, Paul D Jones, James R Sanborn, Bruce D Hammock |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 53
Issue 19
Pg. 7067-75
(Oct 14 2010)
ISSN: 1520-4804 [Electronic] United States |
PMID | 20812725
(Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Analgesics, Opioid
- Anti-Inflammatory Agents, Non-Steroidal
- Piperidines
- Morphine
- Urea
- Carrageenan
- Epoxide Hydrolases
- Adamantane
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Topics |
- Adamantane
(analogs & derivatives, chemical synthesis, pharmacokinetics, pharmacology)
- Analgesics, Opioid
(pharmacology)
- Animals
- Anti-Inflammatory Agents, Non-Steroidal
(chemical synthesis, pharmacokinetics, pharmacology)
- Carrageenan
- Epoxide Hydrolases
(antagonists & inhibitors)
- Humans
- Male
- Mice
- Morphine
(pharmacology)
- Pain
(chemically induced, drug therapy)
- Piperidines
(chemical synthesis, pharmacokinetics, pharmacology)
- Rats
- Rats, Sprague-Dawley
- Solubility
- Structure-Activity Relationship
- Urea
(analogs & derivatives, chemical synthesis, pharmacokinetics, pharmacology)
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