2. Academic Validation
  3. Discovery of Trifluoromethyl Glycol Carbamates as Potent and Selective Covalent Monoacylglycerol Lipase (MAGL) Inhibitors for Treatment of Neuroinflammation

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

  • J Med Chem. 2018 Apr 12;61(7):3008-3026. doi: 10.1021/acs.jmedchem.8b00070.
Laura A McAllister 1,  Christopher R Butler 1,  Scot Mente 1,  Steven V O'Neil 2,  Kari R Fonseca 1,  Justin R Piro 1,  Julie A Cianfrogna 2,  Timothy L Foley 2,  Adam M Gilbert 2,  Anthony R Harris 2,  Christopher J Helal 2,  Douglas S Johnson 1,  Justin I Montgomery 2,  Deane M Nason 2,  Stephen Noell 2,  Jayvardhan Pandit 2,  Bruce N Rogers 1,  Tarek A Samad 1,  Christopher L Shaffer 1,  Rafael G da Silva 2,  Daniel P Uccello 2,  Damien Webb 1,  Michael A Brodney 1
Affiliations

Affiliations

  • 1 Pfizer Worldwide Research and Development , 610 Main Street , Cambridge , Massachusetts 02139 , United States.
  • 2 Pfizer Worldwide Research and Development , 445 Eastern Point Road , Groton , Connecticut 06340 , United States.
PMID: 29498843 DOI: 10.1021/acs.jmedchem.8b00070
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.

Figures
Products