molecules of the month

The Takeda MAGL inhibitor, “compound 4f”, was selected by reviewer Joachim Rudolph. “MAGL (monoacylglycerol lipase) is implicated in neuroinflammation, and inhibitors of this enzyme are of interest as therapeutics in neurodegenerative and other neurological diseases. Most of the advanced compounds, including the clinically evaluated ABX-1431, are irreversible inhibitors, but chronic blockade has been found to lead to undesirable desensitization. There is therefore a need for potent, selective reversible inhibitors of MAGL to assess their clinical viability as an alternative to irreversible inhibitors. This work by Takeda scientists reports new potent reversible MAGL inhibitors with good in vivo PK and PD profiles. The chemical structure of the lead 4f and related compounds also use interesting cyclobutyl/azetidine spiro scaffolds.” The molecule started from an…