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. Rose, T. E., Morisseau, C., Liu, J., Inceoglu, B., Jones, P. D., Sanborn, J. R., & Hammock, B. D. J.~Med.~Chem., 53(19):7067--7075, AMER CHEMICAL SOC, 1155 16TH ST, NW, WASHINGTON, DC 20036 USA, October, 2010. doi abstract bibtex 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-(cyclopropimecarbonyl)piperidin-4-yl)-3-(4-(trifluoromethoxy)phenyllurea (52) showed a 7-fold increase in potency, a 65-fold increase in C-max and a 3300-fold increase in A UC over its adamant:me 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.
@article{Rose:2010bh,
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-(cyclopropimecarbonyl)piperidin-4-yl)-3-(4-(trifluoromethoxy)phenyllurea (52) showed a 7-fold increase in potency, a 65-fold increase in C-max and a 3300-fold increase in A UC over its adamant:me 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.},
Address = {1155 16TH ST, NW, WASHINGTON, DC 20036 USA},
Author = {Rose, Tristan E. and Morisseau, Christophe and Liu, Jun-Yan and Inceoglu, Bora and Jones, Paul D. and Sanborn, James R. and Hammock, Bruce D.},
Date-Added = {2011-10-21 11:40:59 -0400},
Date-Modified = {2011-10-21 11:41:15 -0400},
Doi = {DOI 10.1021/jm100691c},
Isi = {000282544800023},
Isi-Recid = {192124824},
Isi-Ref-Recids = {147511279 176076150 182121750 176444137 84423371 158359759 45846999 185521587 183831730 179058458 84336843 180187839 192124825 157638366 153098605 187134396 171618554 183850311 175028343 152186803 145548521 180977166 144382063 189255095 182974246 176447002 181148881 128660584 100351780 143232394 111238231 125236932 96093751 150121848 145407603 182964762 183401936 190436173 131164989 132733032 189644022 189272084 148780257 64916959 178779606 153739465 184172842 117645840 158445543},
Journal = {J.~Med.~Chem.},
Keywords = {activity cliff},
Month = oct,
Number = {19},
Pages = {7067--7075},
Publisher = {AMER CHEMICAL SOC},
Times-Cited = {4},
Title = {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},
Volume = {53},
Year = {2010},
Bdsk-Url-1 = {http://gateway.isiknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=Alerting&SrcApp=Alerting&DestApp=WOS&DestLinkType=FullRecord;KeyUT=000282544800023}}
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