Soluble epoxide hydrolase (sEH) and fatty acid amide hydrolase (FAAH) metabolize epoxyeicosatrienoic acids (EETs) and arachidonyl ethanolamide (AEA), respectively, and are responsible for the regulation of inflammation, pain and other biological processes. Our recent work has indicated simultaneous inhibition of these two targets through co-administration of two inhibitors is synergistic in the treatment of inflammatory and neuropathic pain. To develop therapeutic approaches with simplified pharmacokinetics and pharmacodynamics, we developed inhibitors with high potency towards FAAH and sEH as a single molecule. Here we describe parallel approaches for the identification and optimization of a lead compound for further testing. The first approach was to screen a library of small molecules known to act on sEH to identify one with cross-potency towards FAAH. The second approach connected well established pharmacophores for sEH and FAAH by a carbon backbone to develop a molecule with high potency towards both enzymes. In this poster, we will describe the synthesis, structure activity relationships and assay development for characterizing inhibitors. These dual inhibitors may be used in the future as powerful therapeutics as well as useful experimental tools for further understanding how these two pathways interact.

Design and synthesis of multi-target inhibitors for soluble epoxide hydrolase (sEH) and fatty acid amide hydrolase (FAAH)

251st National Meeting (2016)

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