Advances in the discovery of fatty acid amide hydrolase inhibitors: what does the future hold?

ABSTRACT

Introduction

Fatty acid amide hydrolase (FAAH) is a membrane-bound enzyme, that inactivates endogenous signaling lipids of the fatty acid amide family, including the endocannabinoid anandamide (N-arachidonoylethanolamine, AEA). The latter compound has been shown to regulate a number of important pathophysiological conditions in humans, like feeding, obesity, immune response, reproductive events, motor coordination, and neurological disorders. Hence, direct manipulation of the endocannabinoid tone is thought to have therapeutic potential. A new opportunity to develop effective drugs may arise from multi-target directed ligand (MTDL) strategies, which brings the concept that a single compound can recognize different targets involved in the cascade of pathophysiological events.

Areas covered

This review reports the latest advances in the development of new single targeted and dual-targeted FAAH inhibitors over the past 5 years.

Expert opinion

In recent years, several FAAH inhibitors have been synthesized and investigated, yet to date none of them has reached the market as a systemic drug. Due to the diligence of inherent redundancy and robustness in many biological networks and pathways, multitarget inhibitors present a new prospect in the pharmaceutical industry for treatment of complex diseases.

KEYWORDS:

• FAAH
• inhibitors
• Anandamide
• single target
• dual targets

Article highlights

• FAAH is an hydrolase that plays a relevant role in the metabolism of fatty acid amides. It degrades important neurotransmitters, such as anandamide, and has been involved in a number of human pathophysiological conditions, thus representing a valuable target for pharmacological research.

• Understanding 3D structure, catalytic mechanism, and regulation of FAAH seems very important for the development of effective compounds able to inhibit its activity, to be used to modulate the in vivo endocannabinoid tone and signaling thereof.

• In the literature, different approaches have led to the synthesis and characterization of many inhibitors of FAAH, with improved selectivity and potency.

• More recently, a new approach has also been used to design better FAAH inhibitors. Indeed, in order to overcome the adverse effects of selective, single-targeted inhibitors, dual inhibitors have been designed to interact with FAAH and additional nodes that control the cascades of pathophysiological processes.

• New single and dual-targeted inhibitors of FAAH discovered in the last 5 years are presented and discussed in this review.

• This box summarizes the key points contained in the article.

Acknowledgments

We wish to thank all of our colleagues who have participated in our studies on FAAH over the last 25 years.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

The authors are grateful for financial support from the Italian Ministero della Salute under competitive Bando Ricerca Finalizzata 2018 (project code RF-2018-12365391) to MM.