Design and Potency of Dual Soluble Epoxide Hydrolase/Fatty Acid Amide Hydrolase Inhibitors.

ABSTRACT: Fatty acid amide hydrolase (FAAH) is responsible for regulating concentrations of the endocannabinoid arachidonoyl ethanolamide. Multiple FAAH inhibitors have been developed for clinical trials and have failed to demonstrate efficacy at treating pain, despite promising preclinical data. One approach toward increasing the efficacy of FAAH inhibitors is to concurrently inhibit other targets responsible for regulating pain. Here, we designed dual inhibitors targeting the enzymes FAAH and soluble epoxide hydrolase (sEH), which are targets previously shown to synergize at reducing inflammatory and neuropathic pain. Exploration of the sEH/FAAH inhibitor structure-activity relationship started with PF-750, a FAAH inhibitor (IC₅₀ = 19 nM) that weakly inhibited sEH (IC₅₀

SUBMITTER: Kodani SD 

PROVIDER: S-EPMC6210075 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature