%0 Journal Article %1 Rose2010sEHInhibitors %A Rose, Tristan E. %A Morisseau, Christophe %A Liu, Jun-Yan %A Inceoglu, Bora %A Jones, Paul D. %A Sanborn, James R. %A Hammock, Bruce D. %D 2010 %J Journal of Medicinal Chemistry %K SAR drug-design medicinal-chemistry pharmacokinetics sEH %N 19 %P 7067-7075 %R 10.1021/jm100691c %T 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 %U http://dx.doi.org/10.1021/jm100691c %V 53 %X 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 Cmax, 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.

@article{Rose2010sEHInhibitors, 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 Cmax, 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. }, added-at = {2017-06-15T01:41:25.000+0200}, 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.}, biburl = {https://www.bibsonomy.org/bibtex/22079b014e9afb7255297620563e4f3d8/salotz}, description = {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 - Journal of Medicinal Chemistry (ACS Publications)}, doi = {10.1021/jm100691c}, eprint = {http://dx.doi.org/10.1021/jm100691c}, interhash = {a24ee5ebe3b9a8acf0b41c9231f9f123}, intrahash = {2079b014e9afb7255297620563e4f3d8}, journal = {Journal of Medicinal Chemistry}, keywords = {SAR drug-design medicinal-chemistry pharmacokinetics sEH}, note = {PMID: 20812725}, number = 19, pages = {7067-7075}, timestamp = {2017-06-15T01:41:25.000+0200}, 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}, url = {http://dx.doi.org/10.1021/jm100691c}, volume = 53, year = 2010 }