Recent advances in the discovery and evaluation of fatty acid amide hydrolase inhibitors

Abstract

Importance of the field: Cannabis has been used for both medicinal and recreational purposes since ancient times. Although cannabinoid-based medicines hold great promise in several challenging therapeutic areas such as pain management and mode control, their development has been hampered by psychoactive and other CNS-related side effects. The identification of fatty acid amide hydrolase (FAAH), a key enzyme responsible for the degradation of endocannabinoids, has brought in tremendous opportunities in that inhibition of FAAH leads to local elevation of endocannabinoids under certain stimuli, thus, avoiding the side effects from global activation of cannabinoid receptors by exogenous cannabimimetic compounds. The search for selective FAAH inhibitors has thus become a strong focus in current drug discovery.

Areas covered in this review: This review summarizes our current understanding of FAAH including its structure, catalytic mechanism and biological functions with emphases on its role in the regulation of endocannabinoids and other signaling lipids. The review then highlights the most recent discovery and biological activities of different classes of FAAH inhibitors. Last, the review discusses challenges and potential drawbacks in the development of FAAH inhibitor-based therapy.

What the reader will gain: Readers will have an overview of FAAH and obtain a rationale on FAAH as an attractive therapeutic target for the development of medicines for treating pain, inflammation, anxiety and other diseases. More importantly, readers will gain knowledge on various newly established FAAH inhibitor scaffolds and their development potentials, and such information will hopefully stimulate ideas for the designing of new inhibitors with superior activity profiles. The discussions on the potential challenges in developing FAAH inhibitors will impose more caution in the decision-making process, thus, lowering the possibility of late stage failure.

Take home message: FAAH is an attractive target for modulating the endocannabinoid system, thus, treating many disease conditions including pain and mode control without the CNS side effects associated with cannabis usage. In recent years, tremendous effort has been focused in the FAAH inhibitor research field, and consequently many novel chemical templates have been discovered. FAAH hydrolyzes several important signaling lipids, but the long-term effects of FAAH inhibition in humans remain to be seen. While it is challenging to identify the right molecule with the right level of intervention of the FAAH function for treating a disease condition, it is possible to avoid mechanism-related undesired effects. With the entry of several compounds into clinical trials, FAAH inhibitor-based medicines are on the horizon.

Keywords::

• α-keto heterocycles
• 2-arachodonyl glycerol
• analgesia
• anandamide
• carbamates
• endocannabinoid
• FAAH
• FAAH inhibitor
• fatty acid amides
• piperidine ureas

Acknowledgements

I thank P Rowland, Structural Biology & Biophysics Department of GlaxoSmithKline in Stevenage, UK for his help with FAAH crystal structural information. I would also like to thank C Arico-Muendel, Molecular Discovery Research Department of GlaxoSmithKline in Waltham, MA, USA for his reading of the manuscript.

Notes

This box summarizes key points contained in the article.