Pharmacokinetic screening of soluble epoxide hydrolase inhibitors in dogs
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- 作者：Hsing-Ju Tsai ; Sung Hee Hwang ; Christophe Morisseau ; Jun Yang ; Paul D. Jones ; Takeo Kasagami ; In-Hae Kim ; Bruce D. Hammock
- 关键词：Soluble epoxide hydrolase inhibitor ; Pharmacokinetics ; Bioavailability ; Epoxyeicosatrienoic acids ; Inflammation ; Cardiovascular diseases
- 刊名：European Journal of Pharmaceutical Sciences
- 出版年：2010
- 出版时间：14 June 2010
- 年：2010
- 卷：40
- 期：3
- 页码：222-238
- 全文大小：1230 K
文摘
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 1 mg/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.