Optimization of a naphthyl amide class identifies potent and selective reversible monoacylglycerol lipase (MAGL) inhibitors

Monoacylglycerol lipase (MAGL) is a serine hydrolase that plays an important role in the metabolism of 2-arachidonoylglycerol (2-AG) and degradation of peripheral monoacylglycerols. Many studies have revealed the potential utility of MAGL inhibitors as anti-inflammatory, anti-nociceptive and even anti-cancer agents. However, the use of covalent irreversible MAGL inhibitors showed an unwanted chronic MAGL inactivation associated with a functional antagonism of the endocannabinoid system. In this context, recent efforts were focused on the development of reversible inhibitors for MAGL. Herein, we reported the design and synthesis of a new series of piperazine derivatives possessing a naphthyl group (7–64), leading to the identification of 55, which displayed high MAGL inhibition with a pIC₅₀ value of 8.0 ± 0.1. We further demonstrated the high selectivity and potency of 55 against endogenous MAGL in mouse brain membranes by using competitive ABPP. Moreover, 55 showed appreciable antiproliferative activity and apoptosis induction, as well as the ability to reduce cell migration in cancer cells such as HT-29. Altogether, these results culminated in the development of the naphthyl amide piperazine derivative 55, which has the potential as a new scaffold for MAGL reversible inhibitor development.