The biological significance of the endocannabinoid system has been studied extensively in recent years. Several endogenous ligands (endocannabinoids) have been discovered to interact with cannabinoid receptors 1 and 2 (CB1 and CB2) and play important roles in regulating a wide range of physiological processes. The endocannabinoid 2-arachidonoyl glycerol (2-AG) is a full agonist of CB1 and CB2, and the principal endocannabinoid found in the brain. 2-AG is rapidly degraded to arachidonic acid (AA) and glycerol by the serine hydrolase monoacylglycerol lipase (MAGL). Inhibition of MAGL has the potential to elevate 2-AG levels which will boost endogenous cannabinoid activity and produce a variety of desirable therapeutic effects. Furthermore, MAGL-mediated 2-AG hydrolysis is an important source of brain AA, a precursor for prostaglandins that promote neuroinflammation and lead to neurodegeneration. Therefore, inhibiting MAGL offers a dual benefit in treating inflammatory disorders. Majority of the reported MAGL inhibitors are irreversible inhibitors. However, chronic inhibition of MAGL by an irreversible inhibitor or genetic deletion of MAGL has been shown to desensitize CB1, which eventually impairs the 2-AG mediated CB1-dependent beneficial effects. It is anticipated that the reversible inhibition mechanism will allow for more precise modulation of 2-AG levels in vivo with an improved therapeutic index. We report herein the discovery of a series of azetidinyl diamide compounds as potent reversible inhibitors of MAGL. Many analogs in this series possessed potent in vitro MAGL inhibitory activity in the enzyme assay and significantly increased 2-AG levels in homogenized rat brain tissue. The lead compound of the series exhibited potent and durable efficacy in a rat complete Freund’s adjuvant (CFA)-induced inflammatory pain model and a chronic constriction injury (CCI)-induced rat neuropathic pain model. Additionally, this lead compound demonstrated very good selectivity for MAGL, and its structure in complex with MAGL was obtained by X-ray crystallography.

Azetidinyl diamides as potent reversible inhibitors of monoacylglycerol lipase (MAGL)

2019 Fall National Meeting

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