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 = 640 nM). Potency
was optimized resulting in an inhibitor with improved potency on both
targets (11, sEH IC50 = 5 nM, FAAH IC50 = 8 nM). This inhibitor demonstrated good target selectivity,
pharmacokinetic properties (AUC = 1200 h nM, t1/2 = 4.9 h in mice), and in vivo target engagement.