%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 }