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Synthesis and Evaluation of Symmetrical and Unsymmetrical Diacyl Ureas, Acyl Urea/Carbamate/Thiocarbamate Derivatives and their Evaluation for FAAH inhibition

Fatty acid amide hydrolase (FAAH) is a serine hydrolase enzyme that metabolizes various lipophilic transmitters, including oleamide, anandamide, and 2‐arachidonyl glycerol. These neurotransmitters are part of the endocannabinoid system (ECS) that comprises a neuromodulatory network involved in regulation of various physiological functions, including appetite, pain, reward, motor control, memory, and mood. Previous studies have shown that enhancing the ECS offers a potential therapeutic target for various psychiatric disorders. An FAAH inhibitor provides indirect modulation of the system, with the added advantage of avoiding undesirable adverse effects associated with the direct receptor agonists. The objective of this study was to synthesize various oleamide analogs and evaluate them for FAAH inhibition. A total of fifty one compounds (1–51) were synthesized using a one‐pot two‐step synthetic scheme. All compounds were evaluated in the in vitro FAAH inhibition assay using human recombinant FAAH enzyme, at 2–100 uM concentrations. Of these compounds, ten analogs showed >50% FAAH inhibition activity at the 50 uM concentration. These compounds serve as leads for structure activity relationship studies to optimize the inhibitory activity and to help design potent and effective FAAH inhibitors to be evaluated in vivo in various animal models of neuropsychiatric disorders.