Epoxyeicosatrienoic acids that have anti-hypertensive and anti-inflammatory properties are mainly metabolized by soluble epoxide hydrolase (sEH, EC 3.3.2.3). Therefore, sEH has emerged as a therapeutic target for treating various cardiovascular diseases and inflammatory pain. N,N′-Disubstituted ureas are potent sEH inhibitors in vitro. However, in vivo usage of early sEH inhibitors has been limited by their low bioavailability and poor physiochemical properties. Therefore, a group of highly potent compounds with more drug-like physiochemical properties were evaluated by monitoring their plasma profiles in dogs treated orally with sEH inhibitors. Urea compounds with an adamantyl or a 4-trifluoromethoxyphenyl group on one side and a piperidyl or a cyclohexyl ether group on the other side of the urea function showed pharmacokinetic profiles with high plasma concentrations and long half lives. In particular, the inhibitor trans-4-4-(3-adamantan-1-yl-ureido)-cyclohexyloxy-benzoic acid (t-AUCB) not only is very potent with good physiochemical properties, but also shows high oral bioavailability for doses ranging from 0.01 to 1mg/kg. This compound is also very potent against the sEH of several mammals, suggesting that t-AUCB will be an excellent tool to evaluate the biology of sEH in multiple animal models. Such compounds may also be a valuable lead for the development of veterinary therapeutics.
%0 Journal Article
%1 Tsai2010sEHPharmacokineticsDogs
%A Tsai, Hsing-Ju
%A Hwang, Sung Hee
%A Morisseau, Christophe
%A Yang, Jun
%A Jones, Paul D.
%A Kasagami, Takeo
%A Kim, In-Hae
%A Hammock, Bruce D.
%D 2010
%J European Journal of Pharmaceutical Sciences
%K in-vivo-screening kinetics-drug-design pharmacokinetics seh-inhibitors seh-ligands
%N 3
%P 222 - 238
%R http://dx.doi.org/10.1016/j.ejps.2010.03.018
%T Pharmacokinetic screening of soluble epoxide hydrolase inhibitors in dogs
%U http://www.sciencedirect.com/science/article/pii/S0928098710001016
%V 40
%X Epoxyeicosatrienoic acids that have anti-hypertensive and anti-inflammatory properties are mainly metabolized by soluble epoxide hydrolase (sEH, EC 3.3.2.3). Therefore, sEH has emerged as a therapeutic target for treating various cardiovascular diseases and inflammatory pain. N,N′-Disubstituted ureas are potent sEH inhibitors in vitro. However, in vivo usage of early sEH inhibitors has been limited by their low bioavailability and poor physiochemical properties. Therefore, a group of highly potent compounds with more drug-like physiochemical properties were evaluated by monitoring their plasma profiles in dogs treated orally with sEH inhibitors. Urea compounds with an adamantyl or a 4-trifluoromethoxyphenyl group on one side and a piperidyl or a cyclohexyl ether group on the other side of the urea function showed pharmacokinetic profiles with high plasma concentrations and long half lives. In particular, the inhibitor trans-4-4-(3-adamantan-1-yl-ureido)-cyclohexyloxy-benzoic acid (t-AUCB) not only is very potent with good physiochemical properties, but also shows high oral bioavailability for doses ranging from 0.01 to 1mg/kg. This compound is also very potent against the sEH of several mammals, suggesting that t-AUCB will be an excellent tool to evaluate the biology of sEH in multiple animal models. Such compounds may also be a valuable lead for the development of veterinary therapeutics.
@article{Tsai2010sEHPharmacokineticsDogs,
abstract = {Epoxyeicosatrienoic acids that have anti-hypertensive and anti-inflammatory properties are mainly metabolized by soluble epoxide hydrolase (sEH, EC 3.3.2.3). Therefore, sEH has emerged as a therapeutic target for treating various cardiovascular diseases and inflammatory pain. N,N′-Disubstituted ureas are potent sEH inhibitors in vitro. However, in vivo usage of early sEH inhibitors has been limited by their low bioavailability and poor physiochemical properties. Therefore, a group of highly potent compounds with more drug-like physiochemical properties were evaluated by monitoring their plasma profiles in dogs treated orally with sEH inhibitors. Urea compounds with an adamantyl or a 4-trifluoromethoxyphenyl group on one side and a piperidyl or a cyclohexyl ether group on the other side of the urea function showed pharmacokinetic profiles with high plasma concentrations and long half lives. In particular, the inhibitor trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB) not only is very potent with good physiochemical properties, but also shows high oral bioavailability for doses ranging from 0.01 to 1mg/kg. This compound is also very potent against the sEH of several mammals, suggesting that t-AUCB will be an excellent tool to evaluate the biology of sEH in multiple animal models. Such compounds may also be a valuable lead for the development of veterinary therapeutics.},
added-at = {2017-06-22T18:57:02.000+0200},
author = {Tsai, Hsing-Ju and Hwang, Sung Hee and Morisseau, Christophe and Yang, Jun and Jones, Paul D. and Kasagami, Takeo and Kim, In-Hae and Hammock, Bruce D.},
biburl = {https://www.bibsonomy.org/bibtex/24975cd8bc383ab2275eefba5b864b004/salotz},
doi = {http://dx.doi.org/10.1016/j.ejps.2010.03.018},
interhash = {b5ffc7c87ea3b94947156b740a7cbd4d},
intrahash = {4975cd8bc383ab2275eefba5b864b004},
issn = {0928-0987},
journal = {European Journal of Pharmaceutical Sciences},
keywords = {in-vivo-screening kinetics-drug-design pharmacokinetics seh-inhibitors seh-ligands},
number = 3,
pages = {222 - 238},
timestamp = {2017-06-22T18:57:02.000+0200},
title = {Pharmacokinetic screening of soluble epoxide hydrolase inhibitors in dogs},
url = {http://www.sciencedirect.com/science/article/pii/S0928098710001016},
volume = 40,
year = 2010
}