Discovery of Trifluoromethyl Glycol Carbamates as Potent and Selective Covalent Monoacylglycerol Lipase (MAGL) Inhibitors for Treatment of Neuroinflammation

Monoacylglycerol lipase (MAGL) inhibition
provides a potential
treatment approach to neuroinflammation through modulation of both
the endocannabinoid pathway and arachidonoyl signaling in the central
nervous system (CNS). Herein we report the discovery of compound 15 (PF-06795071), a potent and selective covalent MAGL inhibitor,
featuring a novel trifluoromethyl glycol leaving group that confers
significant physicochemical property improvements as compared with
earlier inhibitor series with more lipophilic leaving groups. The
design strategy focused on identifying an optimized leaving group
that delivers MAGL potency, serine hydrolase selectivity, and CNS
exposure while simultaneously reducing log D, improving solubility, and minimizing chemical lability. Compound 15 achieves excellent CNS exposure, extended 2-AG elevation
effect in vivo, and decreased brain inflammatory
markers in response to an inflammatory challenge.