Recent findings indicate that increasing levels of epoxides of arachidonic acid (EETs) appear to be new and excellent means to treat both hypertension and vascular inflammation. We demonstrated that in vivo inhibition of soluble epoxide hydrolase resulted in higher levels of EETs and in reduction of blood pressure and inflammation in animal models. Because the effectiveness and length of action were less than optimal for first generation of sEH inhibitors and that the compounds could only be given i.p., the focus of this phase I application is to obtain potent sEH inhibitors with adequate physical properties for oral availability. Toward this objective, we will first produce a fluorescent assay to establish a high throughput screen. A combinatorial library will be made and screened using this enzymatic fluorescent assay. A secondary screen of measurement of physical properties will be used on the new human sEH inhibitors with picomolar Kl, to select a handful of compounds. Physical properties and oral availability will be then measured on this handfull of compounds. In the Phase II work, Arete Therapeutics will use the high throughput assay developed here to widen it search for potentially orally available new inhibitors of sEH. This will be done by screening the combinatorial libraries from the """"""""NIH Roadmap,"""""""" libraries contracted from commercial vendors, and more defined libraries generated in house. In addition, we will take the most potent compounds generated in the Phase I, which also have good physical properties, and synthesize them on a larger scale (0.5-1.0 g) for determining ADME in mice and rats. The compounds with the best pharmacokinetic properties will be used in rat models for hypertension, vascular inflammation and renal inflammation. ? ? ?
| Shen, Hong C; Hammock, Bruce D (2012) Discovery of inhibitors of soluble epoxide hydrolase: a target with multiple potential therapeutic indications. J Med Chem 55:1789-808 |
| Hwang, Sung Hee; Morisseau, Christophe; Do, Zung et al. (2006) Solid-phase combinatorial approach for the optimization of soluble epoxide hydrolase inhibitors. Bioorg Med Chem Lett 16:5773-7 |
| Wolf, Nicola M; Morisseau, Christophe; Jones, Paul D et al. (2006) Development of a high-throughput screen for soluble epoxide hydrolase inhibition. Anal Biochem 355:71-80 |
| Morisseau, Christophe; Newman, John W; Tsai, Hsing-Ju et al. (2006) Peptidyl-urea based inhibitors of soluble epoxide hydrolases. Bioorg Med Chem Lett 16:5439-44 |
| Jones, Paul D; Wolf, Nicola M; Morisseau, Christophe et al. (2005) Fluorescent substrates for soluble epoxide hydrolase and application to inhibition studies. Anal Biochem 343:66-75 |
