The discovery of diazetidinyl diamides as potent and reversible inhibitors of monoacylglycerol lipase (MAGL).

Bin Zhu, Peter J Connolly, Sui-Po Zhang, Kristen M Chevalier, Cynthia M Milligan, Christopher M Flores, Mark J Macielag

Bioorganic & medicinal chemistry letters 2020 Jun 15

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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. Copyright © 2020 Elsevier Ltd. All rights reserved.

Citation

Bin Zhu, Peter J Connolly, Sui-Po Zhang, Kristen M Chevalier, Cynthia M Milligan, Christopher M Flores, Mark J Macielag. The discovery of diazetidinyl diamides as potent and reversible inhibitors of monoacylglycerol lipase (MAGL). Bioorganic & medicinal chemistry letters. 2020 Jun 15;30(12):127198