Development of Potent Inhibitors of Fatty Acid Amide Hydrolase Useful for the Treatment of Neuropathic Pain

The unique role of fatty acid amide hydrolase (FAAH) in terminating endocannabinoid (EC) signaling supports its relevance as therapeutic target. Inhibition of the ECs metabolizing enzymes elicits indirect agonism of CBRs, and therapeutic efficacy, devoid of psychotropic effects. Based on our previous ligands and aiming at discovering new selective FAAH inhibitors, we developed a series of new compounds (5a-l) characterized by functionalized tricyclic scaffolds. All the developed compounds display negligible activity on MAGL and CBRs. The most potent FAAH inhibitors of the newly developed series, 5h and 5i (nanomaolar FAAH inhibitor also some detecting micromolar affinity at CB1R), were selected for further studies. After cellular studies on a neuroblastoma cell line (IMR32) 5h,i and our reference compound 3 demonstrated the lack of any cytotoxic effect and the ability to reduce oxidative stress by decreasing the expression of the redox sensitive transcription factor NF-kB. Encouraged by these data, compounds were studied in vivo and were dosed orally in a mice model of neuropathic pain. At 10 mg/kg all the compounds were able to relieve the hypersensitivity induced by oxaliplatin.