An updated patent review of monoacylglycerol lipase (MAGL) inhibitors (2018-present)

ABSTRACT

Introduction

Monoacylglycerol lipase (MAGL) belongs to the endocannabinoid system and is responsible for the inactivation of endocannabinoid 2-arachidonoylglycerol. Importantly, it was found that MAGL degradation of lipids in cancer cells enhances the availability of free fatty acids for new cellular membrane formation and pro-oncogenic lipid modulators. The multifaceted role of MAGL has greatly stimulated the search for MAGL inhibitors, which could be effective to treat diseases, such as inflammation, neurodegeneration and cancer.

Areas covered

This review covers patents published since 2018 up to now, concerning new MAGL inhibitors and their potential therapeutic applications.

Expert opinion

In the years 2018–2020, several well-known chemical scaffolds of MAGL inhibitors have been further optimized and developed and some new chemical classes have also been identified as MAGL inhibitors. Moreover, an increasing number of scientific publications covering MAGL inhibitors is focused on MAGL-specific positron emission tomography (PET) ligands. The numerous efforts of pharmaceutical companies and academic research groups finalized to find new potent MAGL inhibitors confirm that this research area is rapidly growing. Nevertheless, most of the patented compounds still belong to the large group of irreversible MAGL inhibitors, highlighting that the development of reversible MAGL inhibitors is still an unmet pharmaceutical need.

KEYWORDS:

• Monoacylglycerol lipase
• MAGL
• inhibitors
• cancer
• endocannabinoid

Article highlights

• MAGL inhibitors constitute an attractive research field, thanks to their potential to treat many pathologies, especially neurodegenerative diseases, inflammatory pathologies, metabolic diseases, pain as well as cancer.

• Pros and cons of irreversible and reversible MAGL inhibitions are discussed.

• Recently patented MAGL inhibitors (2018-present) and their potential therapeutic uses are presented.

• Analysis of the chemical structures and recurrent structural motifs used in the design of MAGL inhibitors is performed.

• Selectivity of the patented MAGL inhibitors versus inhibition of other components of the endocannabinoid system (FAAH, ABHD6 and ABHD12) is highlighted.

This box summarizes key points contained in the article.

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.

Additional information

Funding

This paper was funded by the University of Pisa (Progetti di Ricerca di Ateneo, prog. PRA-2018-18) and MIUR (PRIN 2017, project 2017SA5837).