Discovery of novel endocannabinoid level modulators by modification of old analgesic drugs

Fatty acid amide hydrolase (FAAH) is a serine hydrolase that catalyzes the deactivating hydrolysis of the fatty acid ethanolamide family of signaling lipids, which includes anandamide (AEA), an endogenous ligand for cannabinoid receptors. Endogenous FAAH substrates such as AEA serve key regulatory functions in the body and have been implicated in a variety of pathological conditions including pain, inflammation, sleep disorders, anxiety, depression, and vascular hypertension, and there has been an increasing interest in the development of inhibitors of this enzyme. Different structural classes of FAAH inhibitors have been reported including alpha-ketoheterocycles, (thio)hydantoins, piperidine/piperazine ureas, and carbamate derivatives. When tested, these compounds have been shown to be efficacious in models of inflammatory, visceral, and in some cases neuropathic pain without producing the central effects seen with directly acting cannabinoid receptor agonists. An intriguing aspect of FAAH inhibition is that some currently marketed nonsteroidal anti-inflammatory drugs (NSAIDs) have also been shown to be weak inhibitors of FAAH, but can be used as a template for the design of more potent compounds. However, structure–activity relationships of analogues of clinically used NSAIDs with respect to FAAH inhibition have been examined scarcely in the literature. These findings led us to design and synthesis of new series of FAAH inhibitors derivable from conjugation of heterocyclic structures with NSAIDs as profens, fenamates, and new their correlate molecules. In this keynote we report on the synthetic pathways to transform old analgesic drugs into FAAH inhibitors and SAR studies on the new inhibitor series.