1-Aryl-3-(1-acylpiperidin-4-yl)urea inhibitors of human and murine soluble epoxide hydrolase: structure-activity relationships, pharmacokinetics, and reduction of inflammatory pain.
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.
Rose
Tristan E
TE
Department of Entomology and University of California Davis Cancer Center, University of California, One Shields Avenue, Davis, California 95616, USA.
Morisseau
Christophe
C
Liu
Jun-Yan
JY
Inceoglu
Bora
B
Jones
Paul D
PD
Sanborn
James R
JR
Hammock
Bruce D
BD
D000218:Adamantane / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002351:Carrageenan; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy*; D010880:Piperidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
D000701:Analgesics, Opioid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D010880:Piperidines; D009020:Morphine; D014508:Urea; D002351:Carrageenan; D004851:Epoxide Hydrolases; D000218:Adamantane
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