Discovery of trifluoromethyl glycol carbamates as potent and selective covalent monoacylglycerol lipase (MAGL) inhibitors for treatment of neuroinflammation

Laura McAllister, Christopher Butler, Scot Mente, Steven V. O'Neil, Kari Fonseca, Justin Piro, Julie Cianfrogna, Timothy Foley, Adam Gilbert, Anthony Harris, Christopher J. Helal, Douglas S. Johnson, Justin I. Montgomery, Deane M. Nason, Stephen Noell, Jayvardhan Pandit, Bruce N. Rogers, Tarek A. Samad, Christopher L. Shaffer, Rafael G. da SilvaDaniel P. Uccello, Damien Webb, Michael A. Brodney

Research output: Contribution to journalArticlepeer-review

31 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)3008–3026
JournalJournal of Medicinal Chemistry
Volume61
Issue number7
Early online date2 Mar 2018
DOIs
Publication statusPublished - 12 Apr 2018

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