Lu AG06466 is a small molecule inhibitor of monoacylglycerol lipase (MAGL), a serine hydrolase enzyme that regulates metabolic flux of the endocannabinoid 2-arachidonoylglycerol (2-AG). Inhibition of MAGL enhances 2-AG concentrations in the central nervous system (CNS) and potentiates 2-AG signaling through the cannabinoid receptors CB1 and CB2, while also reducing brain concentrations of arachidonic acid and downstream pro-inflammatory prostanoid lipids, resulting in beneficial effects in preclinical models of pain, anxiety, and epilepsy. <br/> <br/>Lu AG06466 is a potent inhibitor of MAGL across species that inhibits 2-AG hydrolysis in human brain and peripheral blood mononuclear cell (PBMC) preparations. Lu AG06466 was extensively profiled by gel- and mass spectrometry-based activity-based protein profiling (ABPP) in human tissue and cells and found to be highly selective. Oral administration of Lu AG06466 to rodents resulted in potent and sustained inhibition of MAGL and elevation of 2-AG in the brain and periphery. A pharmacokinetic/pharmacodynamic (PK/PD) relationship was defined in the rat formalin model of pain and used to predict the clinical dose. <br/> <br/>In Phase 1 clinical trials, Lu AG06466 was tolerated following single- and multiple-ascending doses to healthy human volunteers. Dose- and time-dependent target engagement of MAGL was confirmed in PBMC using a substrate biomarker assay and in the brain using a novel, MAGL-specific PET probe. Currently Lu AG06466 is being explored in several Phase 1b studies in patients with psychiatric and neurological disorders.

Inhibition of monoacylglycerol lipase for the treatment of neurological and neuropsychiatric disorders

ACS Spring 2022

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