Structure-Activity Relationship Studies of Aryl Sulfoxides as Reversible Monoacylglycerol Lipase Inhibitors.

Ming Jiang, Mirjam C W Huizenga, Florian Mohr, Avand Amedi, Renze Bakker, Richard J B H N van den Berg, Hui Deng, Tom van der Wel, Constant A A van Boeckel, Mario van der Stelt

Journal of medicinal chemistry 2024 Jul 25

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Monoacylglycerol lipase (MAGL) is the key enzyme for the hydrolysis of endocannabinoid 2-arachidonoylglycerol (2-AG). The central role of MAGL in the metabolism of 2-AG makes it an attractive therapeutic target for a variety of disorders, including inflammation-induced tissue injury, pain, multiple sclerosis, and cancer. Previously, we reported LEI-515, an aryl sulfoxide, as a peripherally restricted, covalent reversible MAGL inhibitor that reduced neuropathic pain and inflammation in preclinical models. Here, we describe the structure-activity relationship (SAR) of aryl sulfoxides as MAGL inhibitors that led to the identification of LEI-515. Optimization of the potency of high-throughput screening (HTS) hit 1 yielded compound ±43. However, ±43 was not metabolically stable due to its ester moiety. Replacing the ester group with α-CF2 ketone led to the identification of compound ±73 (LEI-515) as a metabolically stable MAGL inhibitor with subnanomolar potency. LEI-515 is a promising compound to harness the therapeutic potential of MAGL inhibition.

Citation

Ming Jiang, Mirjam C W Huizenga, Florian Mohr, Avand Amedi, Renze Bakker, Richard J B H N van den Berg, Hui Deng, Tom van der Wel, Constant A A van Boeckel, Mario van der Stelt. Structure-Activity Relationship Studies of Aryl Sulfoxides as Reversible Monoacylglycerol Lipase Inhibitors. Journal of medicinal chemistry. 2024 Jul 25;67(14):12331-12348