The discovery of diazetidinyl diamides as potent and reversible inhibitors of monoacylglycerol lipase (MAGL).
Basic Information
ID: ALA4627378
Journal: Bioorg Med Chem Lett
Title: The discovery of diazetidinyl diamides as potent and reversible inhibitors of monoacylglycerol lipase (MAGL).
Authors: Zhu B, Connolly PJ, Zhang SP, Chevalier KM, Milligan CM, Flores CM, Macielag MJ.
Abstract: Monoacylglycerol lipase (MAGL) has emerged as an attractive drug target because of its important role in regulating the endocannabinoid 2-arachidonoylglycerol (2-AG) and its hydrolysis product arachidonic acid (AA) in the brain. Herein, we report the discovery of a novel series of diazetidinyl diamide compounds 6 and 10 as potent reversible MAGL inhibitors. In addition to demonstrating potent MAGL inhibitory activity in the enzyme assay, the thiazole substituted diazetidinyl diamides 6d-l and compounds 10 were also effective at increasing 2-AG levels in a brain 2-AG accumulation assay in homogenized rat brain. Furthermore, selected compounds have been shown to achieve good brain penetration after oral administration in an animal study.
CiteXplore: 32334914
DOI: 10.1016/j.bmcl.2020.127198
Patent ID: ┄