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

• Published in: Journal of medicinal chemistry 2024-07, Vol.67 (14), p.12331-12348
• Main Authors: Jiang, Ming, Huizenga, Mirjam C. W., Mohr, Florian, Amedi, Avand, Bakker, Renze, van den Berg, Richard J. B. H. N., Deng, Hui, van der Wel, Tom, van Boeckel, Constant A.A., van der Stelt, Mario
• Format: Article
• Language: English
• Subjects: Animals; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; High-Throughput Screening Assays; Humans; Microsomes, Liver - metabolism; Monoacylglycerol Lipases - antagonists & inhibitors; Monoacylglycerol Lipases - metabolism; Structure-Activity Relationship; Sulfoxides - chemical synthesis; Sulfoxides - chemistry; Sulfoxides - pharmacology
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.4c01037

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.