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

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.