Monoacylglyerol 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 and pain, multiple sclerosis and cancer. Previously, we reported LEI-515, an arylsulfoxide, as a peripherally restricted, covalent reversible MAGL inhibitor that reduced neuropathic pain and inflammation in preclinical models without inducing central nervous system (CNS)-mediated adverse effects. Here, we describe the structure-activity relationship (SAR) of arylsulfoxides as MAGL inhibitors that led to the identification of LEI-515. Optimization of the potency of high throughput screening (HTS) hit 1 yielded ± 43 with high potency (pIC50 = 8.5 ± 0.1). However, ± 43 was not metabolically stable due to its ester moiety, which was required for affinity. Replacing the ester group with α-CF2 ketone as a bio-isoster led to the identification of compound ± 74 (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.
Supporting Information for: Structure-activity relationship studies of arylsulfoxides as reversible monoacylglycerol lipase inhibitors
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