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

Abstract

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.

Inhibitors of lipogenic enzymes as a potential therapy against cancer

“…After a series of optimizations of carbamate derivatives, Pfizer's research group developed the irreversible inhibitor PF-06795071 (32, Figure 5) with an IC 50 of 3 nM for hMAGL. 149 This compound has great drug-like properties due to its novel stereo-defined trifluoromethyl glycol leaving group. PF-06795071 was studied against neuroinflammatory disease and showed high in vivo efficacy, 149 but there are no studies about its use against cancer.…”

“…After a series of optimizations of carbamate derivatives, Pfizer's research group developed the irreversible inhibitor PF‐06795071 ( 32 , Figure 5) with an IC 50 of 3 nM for hMAGL 149 . This compound has great drug‐like properties due to its novel stereo‐defined trifluoromethyl glycol leaving group.…”

“…This compound has great drug‐like properties due to its novel stereo‐defined trifluoromethyl glycol leaving group. PF‐06795071 was studied against neuroinflammatory disease and showed high in vivo efficacy, 149 but there are no studies about its use against cancer. In 2013, a series of urea‐based MAGL inhibitors were developed by Aaltonen et al The most potent of them was JJKK‐048 ( 33 , Figure 5) with an IC 50 value of 0.36 nM against hMAGL 150 .…”

Targeting Endocannabinoid Metabolism: an Arrow with Multiple Tips Against Multiple Sclerosis

“…The search for novel, potent and selective MAGL inhibitors is still ongoing and it is definitely worth mentioning some of the latest developments in terms of lead structures, although these may have not yet been tested in vivo for MS. In 2018, McAllister and colleagues identified a trifluoromethyl glycol carbamate, PF‐06795071 ( 28 , Figure 6), as covalent inhibitor of MAGL potentially useful for the treatment of neuroinflammation [164] . This came from the structural modification of previously reported azetidine‐based compounds able to increase 2‐AG levels in vivo, [159] finally leading to this potent and selective inhibitor (IC 50 h MAGL=3.0 nM, h FAAH=3.1 μM) with improved characteristics and in vitro drug‐like profile.…”

Pyrrolidin‐2‐one linked benzofused heterocycles as novel small molecule monoacylglycerol lipase inhibitors and antinociceptive agents

“…Based on the promising therapeutic benefits of MAGL inhibitors, Abide Therapeutics (California, United States) announces the clinical study of ABX‐1431, which is currently in clinical trials for neurological disorders (Cisar et al., 2018). Moreover, PF‐06795071 (a trifluoromethyl glycol carbamate derivative) was discovered by Pfizer (Massachusetts, United States), as a potent and selective covalent MAGL inhibitor (IC 50 = 3 n m ) for the treatment of neuro‐inflammation (McAllister et al., 2018). Takeda Pharmaceuticals Co. Ltd. (Kanagawa, Japan) identified a potent and reversible MAGL inhibitor (IC 50 = 3.6 n m ), comprising of piperazinyl‐linked pyrrolidin‐2‐one moiety (compound 23; Figure 1).…”