Recent Progress in the Development of Selective MAGL Modulators (2020-2026)

Monoacylglycerol lipase (MAGL) is a key enzyme at the interface between the endocannabinoid system and lipid metabolism, playing a pivotal role in the hydrolysis of the endocannabinoid 2-arachidonoylglycerol and in the regulation of lipid mediators involved in inflammation, pain, neurodegeneration and cancer. Owing to its therapeutic relevance, MAGL has emerged as an attractive pharmacological target, stimulating extensive research efforts aimed at the development of potent and selective modulators of its activity. Advances in medicinal chemistry, together with the increasing application of innovative computational approaches and biochemical methods to assess MAGL activity, have significantly expanded the chemical space of compounds capable of modulating this enzyme. This review provides a comprehensive overview of selective MAGL modulators reported in the scientific literature from 2020 to the present, excluding compounds described exclusively in patent literature and MAGL probes, as this area has been recently reviewed elsewhere, ranging from classical enzyme inhibitors to modulators acting through alternative strategies, such as targeted protein degradation. Overall, this review highlights the structural diversity and the main strategies that have emerged in recent years in modulating MAGL and it aims to guide the rational design of next-generation MAGL-targeting agents.