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

[Image: see text] 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 (IC(50) = 19 nM) that weakly inhibited sEH (IC(50) = 640 nM). Potency was optimized resulting in an inhibitor with improved potency on both targets (11, sEH IC(50) = 5 nM, FAAH IC(50) = 8 nM). This inhibitor demonstrated good target selectivity, pharmacokinetic properties (AUC = 1200 h nM, t(1/2) = 4.9 h in mice), and in vivo target engagement.