Monoacylglycerol Lipase (MAGL) is the key enzyme controlling brain levels of the endocannabinoid 2-arachidonylglycerol (2-AG). MAGL catalyzes 2-AG degradation to arachidonic acid (AA), which is a precursor to pro-inflammatory eicosanoids such as prostaglandins. Inhibiting MAGL has been demonstrated to reduce inflammation in a bi-directional manner. By reducing levels of arachidonic acid, levels of downstream inflammatory mediators are reduced. Additionally, the increased 2-AG levels activate the cannabinoid pathway through CB1 receptor agonism, which has been reported to be beneficial in reducing neuroinflammation. Centrally active MAGL inhibitors with a suitable profile are therefore targeted for the treatment of conditions where neuroinflammation is a significant feature.<br/>We will report the discovery of a novel series of carbamate based irreversible MAGL inhibitors, which feature a heterocyclic core and a trifluoromethyl glycol leaving group. Compounds from this class are in improved physicochemical property space relative to literature tool inhibitors, allowing for improved oral drug properties. SAR efforts to identify an optimum leaving group which balances MAGL potency with serine hydrolase selectivity will be described. A key aspect of leaving group optimization is balancing inherent chemical reactivity, which is a particularly important feature in the design of any irreversible inhibitors to mitigate the safety risks of non-selective covalent binding. Lead molecules from the series with suitable ADME properties such as permeability and brain penetration achieved sufficient PK exposure for in vivo evaluation in models of neuroinflammation.

Identification of potent and selective covalent monoacylglycerol lipase (MAGL) inhibitors for treatment of neuroinflammation

254th National Meeting (2017)

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