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 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.
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)
%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
}