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Discovery of Trifluoromethyl Glycol Carbamates as Potent and Selective Covalent Monoacylglycerol Lipase (MAGL) Inhibitors for Treatment of Neuroinflammation
- Source :
- Journal of medicinal chemistry. 61(7)
- Publication Year :
- 2018
-
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.
- Subjects :
- 0301 basic medicine
Models, Molecular
Arachidonic Acids
Pharmacology
01 natural sciences
Amidohydrolases
Glycerides
03 medical and health sciences
chemistry.chemical_compound
Structure-Activity Relationship
Dogs
Neuritis
Drug Discovery
Structure–activity relationship
Animals
Humans
Enzyme Inhibitors
Rats, Wistar
Neuroinflammation
Brain Chemistry
Trifluoromethyl
010405 organic chemistry
Drug discovery
Anti-Inflammatory Agents, Non-Steroidal
Leaving group
Serine hydrolase
Endocannabinoid system
Macaca mulatta
Monoacylglycerol Lipases
0104 chemical sciences
Rats
Monoacylglycerol lipase
030104 developmental biology
chemistry
Drug Design
Molecular Medicine
Carbamates
Biomarkers
Endocannabinoids
Subjects
Details
- ISSN :
- 15204804
- Volume :
- 61
- Issue :
- 7
- Database :
- OpenAIRE
- Journal :
- Journal of medicinal chemistry
- Accession number :
- edsair.doi.dedup.....67ba4448563e7b467bb25a055a46ddd6