Neuroinflammation is an inflammatory response within the brain or spinal cord. The production of cytokines, chemokines, reactive oxygen species, and secondary messengers mediate this inflammation Neuroinflammation occurs as a consequence of disease or injury resulting in activation of resident immune cells (microglia and astrocytes), production of proinflammatory cytokines and chemokines, and deterioration of the blood-brain barrier. Persistent neuroinflammation can result in neuronal death and ultimately contribute to neurodegeneration.

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). MAGL is a serine hydrolase that regulates the endocannabinoid pathway and arachidonoyl signaling in the CNS. Hopefully, inhibiting MAGL may be a promising therapeutic approach to multiple diseases, such as neuroinflammation. MAGL is a key metabolism enzyme which regulates the network of free fatty acids (FFAs) in numerous aggressive tumors, such as colorectal cancer, neuroblastoma and nasopharyngeal carcinoma, by enabling tumor cells to mobilize and utilize fatty acid (FA) from stored neutral fats.

For this reason, Laura A. McAllister, et al reported the discovery of PF-06795071. PF-06795071 is a potent and selective covalent MAGL inhibitor with an IC₅₀ of 3 nM. In addition to desirable MAGL potency, PF-06795071 retains good selectivity over FAAH, good lipophilic efficiency. Moreover, PF-06795071 achieves excellent CNS exposure, extends 2-AG elevation effect in vivo, and decreases brain inflammatory markers in response to an inflammatory challenge.

Reference:
Sci Rep. 2016 Oct 21;6:35784.