Cyanohydrin based fluorescent substrates of sEH (RMI)

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DESCRIPTION (provided by applicant): Recent findings indicate that increasing the in vivo levels of arachidonic acid epoxides (EEl's) appears to be a new and excellent means to treat both hypertension and vascular inflammation. We have demonstrated that in vivo inhibition of soluble epoxide hydrolase (sEH) resulted in higher levels of EETs and in the reduction of blood pressure and inflammation in animal models. Because the effectiveness and length of action were less than optimal for the first generation of sEH inhibitors, the overall objective of our current work is to develop sEH inhibitors or prodrugs with improved r in vivo potency. Towards this end, we will first produce a fluorescent assay for sEH based on the liberation of cyanohydrin upon epoxide hydrolysis. The assay will be optimized toward establishing a high throughput screen in 96- and 384-well formats. The assay will be validated against our library of sEH inhibitors and a larger commercial combinatorial library. Ultimately, this assay will be used to develop new potent 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.