The discovery of diazetidinyl diamides as potent and reversible inhibitors of monoacylglycerol lipase (MAGL) |
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| Affiliation: | 1. Department of Chemistry, Physics, and Atmospheric Sciences, Jackson State University, Jackson, MS 39217, USA;2. Department of Biochemistry, Federal University of Technology, Akure, Nigeria;1. Laboratory for Radiopharmaceutical Research, Department of Pharmaceutical and Pharmacological Sciences, Campus Gasthuisberg O&N2, Herestraat 49 Box 821, BE-3000 Leuven, Belgium;2. Department of Nuclear Medicine & Molecular Imaging, UZ Herestraat 49, 3000 Leuven, Belgium;3. Institute of Biomedicine, Faculty of Health Sciences, The University of Eastern Finland, Finland |
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| 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. |
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| Keywords: | Monoacylglycerol lipase (MAGL) MAGL inhibition Reversible MAGL inhibitor 2-Arachidonoylglycerol (2-AG) |
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